Tsunade

is one of Konohagakure's legendary Sannin. Though celebrated as the world's most powerful kunoichi and its greatest medical-nin, Tsunade abandoned the life of the ninja for many years in pursuit of other goals. She is eventually persuaded to return to Konoha and becomes its, where her skills were invaluable to the village.

Background
Tsunade is the first granddaughter of the First Hokage: Hashirama Senju, and his wife Mito Uzumaki, as well as the grandniece of the Second Hokage: Tobirama Senju, leading others to call her. In her childhood, she was spoiled by Hashirama, who doted on his first grandchild, and even picked up his habit for gambling. She, along with Jiraiya and Orochimaru, are also former students of the Third Hokage. Like Team Kakashi, Tsunade and her team-mates were given the bell test, which Jiraiya failed and was subsequently tied to a stump. Tsunade taunted him before leaving with Orochimaru.

At some point, she almost killed Jiraiya after he was caught peeping on her while she was in the hot springs, breaking both of his arms, six of his ribs and ruptured several internal organs. Ever since then, Jiraiya has been very careful to suppress his perverted ways around Tsunade. Jiraiya mentions that this is one of only two times he has ever been close to death.

During the Second Shinobi World War, prior to meeting the Ame Orphans, Tsunade and her team-mates fought Hanzō, who gave them the title of Konoha's, the Sannin, as a reward for surviving their battle with him while everyone else in the group died easily. On her own merit, Tsunade became famous for frequently counteracting all of Chiyo's poisons, earning the Sunakagure kunoichi's contempt for it. Furthermore, according to Jiraiya, Tsunade's unrivalled skills as a combatant and a medic were the reason Konoha won the war. However, Tsunade suffered painful losses prior to the Second Shinobi World War ending.

The tragic turn of events began when her younger brother, Nawaki was killed in action the day after his twelfth birthday, receiving their grandfather's crystal necklace which she gave him in the hopes that it would help him achieve his dream of becoming Hokage. This event resolved Tsunade to advocate for the inclusion of medical-nin to be incorporated into teams that were on the battlefield but unable to as Hiruzen informs her the conflict makes it impossible for them to utilise resources or the time to train such ninja. It was by that time that a discouraged Tsunade met Dan Katō who seconds her request of focusing on finding ways to save their comrades' lives on the battlefield.

In time, finding herself and Dan have similar ideals, Tsunade fell in love with him. As a sign of her affection, and in the hopes that this time it would help make his dreams come true, Tsunade gave him Hashirama's necklace prior to his death, with the necklace returning to her possession, rumoured as a cursed item that kills anyone other than Tsunade who wears it. Developing hæmophobia which renders her unable to take part in any more battles, the deaths of both Nawaki and Dan disillusioned Tsunade to see the Hokage title as nothing but a fool's position. With these changes of ideals, Tsunade left Konoha with Dan's niece, Shizune, taking her on as her apprentice who became one of the few people Tsunade truly trusts. Tsunade also came to own a pet pig, Tonton, which she leaves mostly to Shizune's care.

In the anime, Tsunade met the Fourth Raikage, after he and his followers were ambushed by the ninja of the Nokizaru Group and needed her help to remove an Exploding Insects implanted in A and one of his followers. However, due to her phobia, Tsunade had Shizune carry out the surgery while she oversaw it until a bit of blood splattered on her and she excused herself from the room, going outside to calm herself down.

Personality
During her childhood, Tsunade was spoiled greatly by Hashirama so much that he couldn't help but wonder if the village was all right with her being the Fifth Hokage. However, as she grew older, she became well-disciplined and even greatly contributed to Konoha's victory in the Second Shinobi World War.

When she was first introduced, Tsunade was cynical of anyone with dreams, especially those who want to become Hokage, believing that it was a futile dream. This mindset was expressed when Tsunade not only declined the offer of becoming the Fifth Hokage, but claimed that anyone who wanted to become Hokage was a fool. After meeting Naruto, she realises that this cynicism is insulting to the memories of both Dan and Nawaki. After seeing Naruto's conviction to become Hokage and proving her wrong in his ability to learn the Rasengan, she has a change of heart. Despite her still blunt attitude towards Naruto, she has come to care for him deeply and puts her faith in him for the future, even agreeing to take on the mantle of Hokage herself, carrying on the dreams of Dan and Nawaki. As Hokage, Tsunade has shown the same level of loyalty to the village that previous Hokage held; during Pain's assault on Konoha, she released all of her chakra in order to save the lives of thousands of people within Konoha, at great personal risk. When she first became Hokage, her duties were to heal every injured person which she did with the exception of Rock Lee, who needed surgery. Upon realising the surgery gave Lee a 50/50 chance of survival, she spent hours tirelessly studying human anatomy to find a way to emulate Kabuto's healing powers to increase his chances of surviving the surgery. Tsunade also has a great deal of faith in the next generation, and sees the potential that Naruto and the rest of the Konoha 11 hold. Even after stepping down as Hokage, Tsunade continues to aid the village in every way she can, as seen when she assisted the villagers in evacuating from the falling meteors.

Tsunade typically projects a tough demeanour, even when facing great personal difficulty. She readily criticises others for their faults, such as Naruto's immaturity or Jiraiya's perversion, though her habits are rarely any better. Another trait of Tsunade is her monstrous and quick temper. Many fear her because of this, such as Shizune, Jiraiya, and Sakura, the latter of whom has on several occasions warned Naruto on how to behave in her presence. Despite her temper, Tsunade is a reasonable person. She was willing to listen to Pain and even admit Konoha's past faults though he was the one who killed Jiraiya and was threatening her own village. Beneath this tough exterior, Tsunade truly loves her village and its people and will at times show sympathy for others, consoling Shikamaru that, while he failed his mission to return Sasuke Uchiha to Konoha, all of his team-mates survived. This is also shown when she worked hard in order to help heal Rock Lee, so that he might continue to be a ninja. In life-threatening or important situations that involve putting someone she cares for in danger, she tends to get angry with people who disagree with her plan, such as the restrictions the Konoha Elders placed on Naruto, or the argument on whether Naruto and Killer B should participate in the Fourth Shinobi World War, even calling Gaara a "child" when he disagreed with her. As with all Hokage before her, Tsunade deeply believes in the Will of Fire.

Tsunade also has a firm belief that Naruto, and all jinchūriki, are people rather than instruments of war. She has always voiced that Naruto is a great ninja and should be used by the village as any other ninja would be. This value is so strong in Tsunade that she yelled at the other Kage for not allowing Naruto and Killer B to fight in the Fourth Great Shinobi War. Although she eventually agrees to keep the jinchūriki away from the battles, she is outraged when A decides to kill Naruto to prevent him entering the war. Tsunade then turns on A, saying that they need to use the jinchūriki in the war if they are going to win. This shows her great faith in Naruto to end the war, as she was even willing to challenge the Raikage in order to let Naruto and B pass. When Obito was defeated, which led the rest of the Allied Shinobi Forces attempting to kill him, Tsunade stopped them out of knowledge that Naruto found redemption for Obito.

As a legendary medical-nin, Tsunade truly is a role model for other medical-nin to follow. Her first priority in any situation is the lives of others. She created four rules that guides other medical-nin on the battlefield, one of which is that they should never give up on treating their comrades as long as they are still breathing. When Pain attacked Konoha, she actively took on the role of a medical-nin, healing all the injured shinobi while even having Katsuyu protect the corpses of the deceased, and did all she could to protect the village, even if it meant that she had to risk her own life. Because of this, even the persons that were later revived by Nagato, had bodies to return to. In the fight against an extremely powerful opponent like Madara Uchiha, she was the one who received the worst injuries. However, she was still the only one who was able to regain consciousness, and still put the lives of the other Kage, before her own.

Tsunade is also a compulsive gambler, a trait she inherited from Hashirama, with a losing streak due to her terrible luck. As a result, she has been elevated to a comical status as because of the gross profits others have made off of her misfortune and gambling addiction. In the rare instances that Tsunade hits a winning streak, she takes it as a bad omen that will eventually affect her, or her comrades. However, using this to her advantage she can take steps to protect herself and her comrades. The symbol on the back of her coat,, means "gamble", or "wager", as gambling is one of her favourite pastimes.

Despite Tsunade shunning all of Jiraiya's romantic advances over the years, as she was still in love with Dan even after his death, her being trapped in the Infinite Tsukuyomi showed her greatest desire being together with him, she still cared very much for him as one of her oldest friends. While he was in Amegakure investigating Pain, she bets that he will die so that her terrible luck will ensure he survives. When she finds out he has died, she thinks back on their time together and mourns privately for the loss of her dear friend.

Appearance
Tsunade is a light-skinned woman of average height with brown eyes and straight, blonde hair. Her hair is waist-length with shoulder-length bangs framing both sides of her face. As a child, she tied her hair in twin short pigtails before becoming Hiruzen's student when she then wore her hair in a high ponytail. As an adult, Tsunade usually ties her hair into two loose ponytails. Some time after leaving the village, she obtained a violet rhombus mark on her forehead similar to her grandmother's, which she uses as a chakra gathering point known as the Strength of a Hundred Seal.

Now in her fifties, Tsunade has aged considerably. However, she maintains the appearance of her younger self through a unique and constant Transformation Technique. In her prime, the appearance she normally takes, she has a slender frame. Despite being known as flat-chested in her childhood, she now has a rather large bust; 106 centimetres in circumference, according to Jiraiya. Her beauty has been pointed out several times and she's been called the most beautiful kunoichi in the world by several characters.

She often wears a grass-green haori with the kanji for written in black on the back, inside a red circle. Underneath she wears a grey, kimono-style blouse with no sleeves, held closed by a broad, dark bluish-grey obi that matches her pants. Her blouse is closed quite low, revealing her sizeable cleavage. She wears open-toed, strappy black sandals with high heels and red polish on both her fingernails and toenails. She also wears a soft pink lipstick. She also used to wear her grandfather's necklace in clear view on her chest, before giving it to Naruto.

Abilities
As one of the Legendary Sannin and the Fifth Hokage, Tsunade is reputed to be one of the most powerful kunoichi in ninja history, greatly admired around the world. A testament to her skill, Tsunade is accredited as the reason Konoha achieved victory in the Second Shinobi World War. She is a remarkable combatant and medical-nin and is also hailed as the world's strongest kunoichi, which has lead to many younger kunoichi to look up to her. Jiraiya commented that no one could stand equal to her in terms of combat and medical prowess. Despite being out of practice, she managed to overwhelm the prodigy, Kabuto Yakushi, and even defeat the infamous Orochimaru when each were equally handicapped. Tsunade's overall might was even acknowledged by Madara Uchiha after holding her own against him alongside the other Kage when they battled.

Physical Prowess
Tsunade's trademark ability is her immense raw strength, with which she was able to crush rock with a single hand. An opponent struck by her attacks could suffer damage ranging from broken bones, ruptured organs, or even death, as Jiraiya learned from his perverted actions in his youth. Jiraiya even notes that on one occasion, Tsunade struck him with such power that he ended up being thrown 100 metres away. In the anime, when facing the Fourth Raikage in an arm-wrestling match, the latter had to resort a feint to throw her off-balance in conjunction with his high-speed to defeat her, as he was being overpowered.

Tsunade's durability is also considered to be one of her most remarkable physical traits. This durability allowed her to survive the life-risking Heavenly Transfer Technique with only minor injuries in the process, something Mabui, the technique's user, deemed impossible for anyone but the Third Raikage. She was also take an attack from a powerful Yasaka Magatama fired at close-range without getting damaged. A further testament to this trait was her ability to still move after having her arm, leg and intercostal muscles torn — something Kabuto noted was an impressive and praise-worthy feat no ordinary person could achieve.

While a medical-nin normally tries to avoid direct battle, Tsunade's taijutsu has been considered unsurpassed, which she uses mainly to intimidate her opponents from approaching her in order to carry out her primary duties as a medical-nin. When entering battle directly, she is a force to be reckoned with. In battle, Tsunade has displayed great speed, flexibility, and ferocity. She was able to incapacitate Shizune with a quick strike before the latter could react. In her battle with Kabuto Yakushi, she showed enough skill to evade his strikes and throw swift counter attacks, giving the younger shinobi very little time to react. Another testament to her speed, was her ability to get up off of her feet, appear behind Kabuto and then use the Body Pathway Derangement technique on him during the brief interval when he thought she had been incapacitated. . She could also throw herself at Orochimaru and deliver a powerful kick, knocking him backwards before he had any time to react, and even intercept Manda while he was mid-bite, using Gamabunta's sword no less. Before Mei or any of the other Five Kage could react, Tsunade intercepted all five of Madara's flame dragons dissipating them all with her fists in quick succession.

Likewise, Tsunade showed herself to be very nimble, being able to attack from various angles, even while in mid-air, to effectively pressure her opponents or keep up with faster allies to coordinate devastating attacks. As a field medical-nin, Tsunade is reputed to be highly skilled in the art of evasion; skills she deems necessary for field medics since their healing abilities would be pointless if they are unable to survive and be the last to die. These are skills and views she instilled in her own disciples, and were witnessed most notably during her scuffle with Naruto in Part I, where she displayed excellent dexterity and reflexes despite having consumed copious amounts of alcohol.

Life Force and Chakra Control
Stemming from her Senju and Uzumaki lineage, Tsunade has been shown to have a powerful life force; allowing her to survive most otherwise fatal injuries and continue battling even under the most dire and strenuous of situations. She also has a high tolerance for physical pain, as she was able to deliver a heavy kick to Orochimaru after being sliced in her shoulder, and stabbed through her chest. Throughout the fight with Orochimaru, she was able to push herself to fight on despite being tired and injured. She was also able to continue fighting with extreme force against Madara's Susanoo army despite being impaled through her abdomen with two giant Susanoo blades. Even after being bisected, she was still able to survive the ordeal, regain consciousness, summon Katsuyu, and kept herself alive for what seemed like several hours, all the while healing the other Kage, a task she completed after she herself was healed by Karin under the orders of Orochimaru.

Tsunade has immense supplies of chakra. She was able to simultaneously heal a large number of people using the Mystical Palm Technique with the help of Katsuyu over a long period of time, despite the large amount of chakra the technique consumes. Even more impressive than her chakra reserves is Tsunade's control. Since at a young age, Tsunade excelled in all forms of chakra manipulation; even able to maintain multiple techniques at once. Her innate talent for it allows her to gather her chakra from any part of her body with such precision and perform any technique to their maximum potential without any wasted chakra or timing. Her signature ability with chakra control is to instinctively amplify her already legendary strength with chakra control to monstrous levels, allowing her to perform feats such as being able to launch her targets several metres with a mere finger flick or create fissures with a single finger jab at the ground. She could launch Gamabunta's tantō into the air and then guide it down right into Manda's mouth. Perhaps most notable of all of her feats of strength, was her ability to shatter Madara Uchiha's ribcage Susanoo with just a couple of strikes — something few other characters have been able to replicate without powerful enhancements, and then later went on to knock down a complete version of the Susanoo with single punch. This is done by building up and releasing her chakra with precise timing upon impact, making it effortless for her to decimate any target.

The peak of her chakra control, is her ability to form the Strength of a Hundred Seal, which allows her to store massive amounts of chakra on a point on her forehead and then release it; a feat that only Tsunade and her own student have accomplished, further showing the difficulty of attaining it. Upon its release, Tsunade can either use the stored chakra to facilitate the activation of one of her techniques such as the Creation Rebirth and Ninja Art Creation Rebirth — Strength of a Hundred Technique which makes her virtually immortal in battle or simultaneously heal and protect the entire citizens of Konoha from a very powerful attack such as Pain's Shinra Tensei. She is also able to transfer chakra to others as seen when she gave Ōnoki some of her chakra in order to facilitate his large-scale Dust Release: Detachment of the Primitive World Technique. With the massive amounts of chakra released from her seal powering her Chakra Transfer Technique, Ōnoki's own technique increased in volume to be at least as much as one hundred times its usual size. The more chakra Tsunade stores up inside her seal, the more ferocious her techniques, which gives her incredible combat potential.

Transformation Technique
Even though she is in her early fifties, Tsunade's Transformation Technique makes her appear as if she were still in her twenties as Jiraiya noted she was not one to "age gracefully". She readily alters what age she appears in order to avoid her gambling debts. Tsunade's transformation is somewhat different from a normal transformation, as it seems to be permanent, not getting dispelled when she is slashed or injured, and she apparently does not need to exert any effort to stay transformed. She is able to maintain her transformation even while asleep. The transformation dispels when she runs out of chakra from the Strength of a Hundred Seal, reverting her to her natural appearance.

Medical Ninjutsu
Much of Tsunade's fame comes from her being able to perform any procedure flawlessly to cure and heal injuries that others would consider impossible or a lost cause. She can do so through the usage of no more than chakra or basic tools. Upon her return to Konoha, she quickly healed the psychological damage done to Sasuke by Itachi Uchiha's Tsukuyomi, fixed the damage done to Lee's spine, and later counteracted the effects of the Three Coloured Pills on Chōji Akimichi, something his father stated would have been impossible if she weren't there. Tsunade has also been noted to be capable of making powerful sleeping potions that are also colourless; Jiraiya notes she is the only one in the world who could spike a drink without a ninja knowing it was drugged.

With her remarkable knowledge of the human body and converting her chakra into electricity, Tsunade is capable of sending electric waves into the opponent's nervous system by striking the back of the neck. This then scrambles the electric signals within them and disrupts the way their body moves, such as attempting to move the right hand would cause the left leg to move instead, and so on. It is unknown if this is Lightning Release. In a similar manner, Tsunade has also shown the ability to use medical ninjutsu adversely and use it to harm, even kill, instead of heal. She can use a single chakra-infused strike to effortlessly cause internal damage or incapacitate a target as she did the latter to Shizune when she tried to stop Tsunade from meeting with Orochimaru. Tsunade is also able to create a chakra scalpel both for surgery and to inflict internal lacerations and even attack the internal organs.

The most extreme example of her medical prowess is her Creation Rebirth, a technique that makes use of the massive amounts of chakra stored in her Strength of a Hundred Seal to continuously create new cells in her body, healing any wound and even growing back missing organs. It gives her a form of "immortality" in battle that even Orochimaru expressed envy for. However, as cells can only divide and be created a set amount of times, the technique shortens her life-span. Because of the risk associated with the technique, Tsunade only uses her regenerative techniques in extremely desperate situations. These techniques are considered to be the absolute pinnacle of medical ninjutsu, and Tsunade developed them under the resolution of protecting those dear to her. Indeed, Tsunade created an extension of the Creation Rebirth known as the Ninja Art Creation Rebirth — Strength of a Hundred Technique, which causes the seal to extend all the way down her body. While this technique is active, any wounds Tsunade receives will heal instantaneously, without the need to make hand seals or even a conscious effort.

She was also able to instantly heal Shikamaru, who was suffering from severe chakra depleting simply by laying her hands on him.

Summoning Technique
Tsunade can summon slugs of varying sizes, although she has only ever been seen summoning Katsuyu. The slugs' primary abilities seem to revolve around spitting acid and splitting into smaller slugs. Tsunade apparently has a mental connection with Katsuyu, as she was able to get reports and send out messages through Katsuyu during Pain's assault on Konoha. Tsunade can transfer her chakra to a large number of slugs over long distances, to restore their chakra or even perform techniques on them. By having the slugs spread out and attach themselves to wounded individuals, Tsunade is then capable of healing multiple injuries at different locations simultaneously. This technique proved particularly helpful during Pain's invasion which helped Tsunade preserve the life of the villagers even after a devastating attack by the enemy forces.

Nature Transformation
Tsunade has proficiency in four natures: Lightning Release, Fire Release, Water Release, and Earth Release. She is also capable of utilising Yin Release and Yang Release.

Intelligence
While normally appearing carefree or short-tempered, Tsunade is a capable leader. A keen thinker, Tsunade is also highly observant and analytical, allowing her to see through most deceptions, and is rarely caught off-guard. Most commonly, Tsunade will choose the best ninja available to construct a team after looking over the assigned mission. In the anime, she was able to analyse and replicate the basic mechanics of Kabuto's regeneration technique to better the chances of Rock Lee's life-risking surgery being a success.

Her intelligence is most renowned as the best in the world for her expertise in all areas of medicine. She has been credited with creating the official medical-nin system and the laws that govern them. She can immediately determine what kind of injuries or illness (physical or mental) a person has from a single glance. In addition to this, Tsunade seems to have a vast knowledge of poisons and herbal medicine, as noted by Chiyo who stated that during the Second Great Shinobi War, Tsunade was the only one capable of countering all her poisons perfectly. She also has remarkable knowledge of the human psyche, as she was able to effortlessly undo the damage to Kakashi and Sasuke's minds inflicted by Itachi's Tsukuyomi in a matter of seconds. Tsunade has also proven to be a very capable teacher, having single-handedly trained Sakura and Shizune and passed on much of her knowledge make them become two of Konoha's best medical-nin and field support.

In battle, she has shown great ingenuity, able to quickly pick up on her opponent's fighting style and battle pattern to better avoid damage and plan her attacks around that. These traits are to keep herself alive in battle so she may heal her team-mates; things she drilled into Sakura while training her. Her mental fortitude is also noteworthy, as she overcame her paralysing fear of blood through willpower alone, something every eyewitness found miraculous.

Other Skills
Tsunade is also well-versed in fūinjutsu, capable of developing an S-rank seal that continuously stores up chakra for various reasons including using the high-level techniques such as the Creation Rebirth and Ninja Art Creation Rebirth — Strength of a Hundred Technique which she also created. After the Fourth Shinobi World War, she learned how to create organic and fully-manoeuvreable prosthetics from the cells of her grandfather Hashirama Senju. In the anime, she was also stated to be capable of using the Five Elements Unseal technique.

In the anime, Tsunade demonstrated noticeable skill in a variety of other areas. When dealing with the Legendary Stupid Brothers, her skill in genjutsu was great enough to bind the immensely strong duo at once. She was also able to use Space–Time Ninjutsu to send one of Katsuyu's divisions to Team Three's location despite the great distance. She is also highly adept in barrier ninjutsu; able to design the high-level Four-Corner Sealing Barrier from scratch, which can be used to seal a tailed beast.

Search for Tsunade
After his failed Konoha Crush cost him his arms in the aftermath of his fight with Hiruzen, Orochimaru sought out Tsunade to heal his arms. Declining at first while noticing is arms, Kabuto Yakushi complemented Tsunade's talent while saying that she's the only one in the world who can cure Orochimaru or kill him. Inspecting the injury, Tsunade learns that it was inflicted on her former team-mate by Hiruzen, whom Orochimaru killed in battle. Shocked upon hearing that revelation, Tsunade attempts to kill Orochimaru before he offers to use Impure World Reincarnation to bring back Dan and Nawaki as payment for her services. Seeing that she was tempted by this offer, Orochimaru left her a week to consider his proposal.

Soon afterwards, Tsunade was approached by Jiraiya, who wanted her to become the next Hokage. After she disrespectfully turns down the offer, an enraged Naruto challenges Tsunade to a fight for her ridiculing of the title. Though she easily beats him in the match, Tsunade shows interest at Naruto's attempt of using the Rasengan and makes a bet with him: she would give him Hashirama's necklace if he could master the technique within a week and he would give her all the money he had on him should he fail. Naruto accepted the bet, and Tsunade kept a careful eye on Naruto's progress throughout the week while contemplating Orochimaru's offer. When the week was up, and Naruto appeared to have failed in mastering the technique, she drugged Jiraiya so he would not meddle and went to meet Orochimaru.

Though it seemed she was able to heal Orochimaru, having him promise not destroy Konoha once his arms were healed, Kabuto exposes Tsunade's actual intent to kill Orochimaru. Her motives known, Tsunade revealed that she knew Orochimaru has no intention of honouring his promise to leave Konoha alone and that she couldn't bring herself to let him attack the village, even if it meant seeing Nawaki and Dan again. While she had tried to forget this fact over the years, Naruto's determination and desire to be Hokage reminded her of their dreams, and she had decided to do whatever was necessary to protect those dreams.

With that, Tsunade attacked Orochimaru, though Kabuto fought her in his place. However, realising that he is completely outmatched, Kabuto slits his wrists to use Tsunade's hæmophobia against her before Shizune and Naruto came to her rescue. While he and Shizune were easily defeated, despite Tsunade telling him to run, Naruto was able to overcome his injuries and manages to defeat Kabuto with a perfected Rasengan in his effort to protect her. As Naruto collapsed and in critical condition, Tsunade manages to heal him and giving him Hashirama's necklace in hope he would become a Hokage.

Orochimaru, worrying about what kind of threat Naruto might become when he got older, attempts to kill him, though Tsunade blocks that attack with her body. When inquired as to why she was protecting Naruto, Tsunade replies that Naruto would someday be Hokage, and that she would not allow him to die before that happened. With that, Tsunade accepted the title of Fifth Hokage while overcoming her fear of blood to eliminate Orochimaru. Joining forces with the still drugged Jiraiya, the two attacked Orochimaru. After a battle of summons, Tsunade dealt the finishing blow to Orochimaru. Defeated, Orochimaru escaped, vowing to destroy Konoha once he'd healed himself. Once Naruto recovered, the group returned to Konoha where Tsunade begins her term while secretly believing that Naruto would someday become her successor. Also, like with Nawaki and Dan before Naruto, Tsunade gives him a kiss on the forehead to show her faith in him.

Soon after arriving in Konoha to take her place as Hokage, Tsunade healed the mental injuries inflicted by Itachi Uchiha's Tsukuyomi on Kakashi Hatake and Sasuke Uchiha. She also gave a grim prognosis on Rock Lee's condition. She stated that the only procedure that could allow him to return to duty as a ninja was one that she alone was capable of performing, and it only had a fifty percent success chance that could prove to be fatal for Lee. Not wanting to take such a risk, Tsunade advised Lee that it was best that he retire as a ninja and find another profession. However, upon seeing Lee's resolve to become a ninja and the Will of Fire which burned within him, she decided to conduct the surgery. In the anime, while Lee is struggling to decide what he should do, Tsunade looked into ways to improve his chance of survival. Thinking back to how she had seen Kabuto withstand Naruto's Rasengan, Tsunade used Kabuto's technique as a basis to improve Lee's chances of survival from fifty to fifty-eight percent. Lee finally agreed to undergo the procedure, and survived.

Sasuke Recovery Mission
When Sasuke defected from the village so that he could go to Orochimaru, Tsunade was forced to send out a group of genin to try and stop and retrieve him, due to lack of manpower. She also used Konoha's reacquired alliance with Sunagakure to call in a favour for reinforcements, hoping to give the retrieval team some back-up. Despite her efforts, the group ultimately failed, and Tsunade helped in healing their mortal injuries, bringing them back to full health. She was particularly instrumental in the healing of Chōji, mixing the antidote to the side effects of the Three Coloured Pills that she got from the medical encyclopaedia kept by the Naras; a fact Chōza gratefully stated. In the aftermath of Sasuke's betrayal, Sakura Haruno asked to become Tsunade's apprentice, which Tsunade gladly accepted.

In the anime, before Naruto left with Jiraiya to train, she intentionally placed Naruto on as many missions as possible to keep Naruto busy until Jiraiya came back, to prevent him from going after Sasuke himself. In the anime, when Naruto finally departed, Ino Yamanaka asks the Sannin to train her in medical ninjutsu, to which she presumably accepts.

Mizuki Tracking Mission
In the anime, when the Legendary Stupid Brothers escape from prison, she convinces them to surrender with a quick display of genjutsu and her strength.

The Appearance of Strange Visitors
In the anime, Tsunade learned from Kakashi that two strangers entered the village impersonating Rock Lee and Might Guy. Deciding to have fun with the two, Tsunade pretended to believe their disguises and had them due many arduous tasks for her, even having them help Katsuyu when she got sick. Ultimately, Tsunade's cruel jokes made the men leave the village in horror.

Interlude
During the next two years, Tsunade continued training Sakura in medical ninjutsu, along with keeping up her duties as Hokage. Shortly after Naruto and Jiraiya left, Ino Yamanaka appeared with a similar desire to Sakura for learning medical ninjutsu under Tsunade. Intrigued, Tsunade decided to test Ino, giving her three months to master resuscitation of an octopus to officially become Tsunade's student alongside Sakura. At the same time, she tasked Sakura with memorising a large shelf of medical books. While keeping quiet about it, she noticed that the strong rivalry between Sakura and Ino helped in pushing the duo into improving. Ultimately, Ino passed her challenged and Tsunade began training Ino as well. Despite this, Tsunade decided to not train Ino beyond basic medical ninjutsu, feeling that it would simply better help her in learning her clan's secret techniques in the future.

In Naruto's Footsteps: The Friends' Paths
In the anime, about two years after Naruto and Jiraiya left, Tsunade decided to organise the next Chūnin Exams early within Konoha, sponsored alongside Suna with their new ties alongside the Suna-nin. While wanting to also to restore Konoha's reputation after the interruption of the last Chūnin Exam by Orochimaru's invasion, she also saw this as an opportunity to lure out the Akatsuki. While Gaara, now the Kazekage, agreed with this, he expressed his desire to host the exams personally in Suna. Ultimately, it was agreed to host the first exam within Konoha and the second exam within Suna. While Tsunade sent out an invitation to the other ninja villages, the other Kage all rejected the offer. At the same time, Tsunade sent Kakashi to Amegakure to deliver the invitation and investigate the rumours of a coup d'état on Hanzō. Later, Tsunade received word that Amegakure would join the exams. While this implied that the village was still its usual state, Tsunade was convinced it was a cover-up. As word that Amegakure, Kusagakure and Takigakure would also join the exams, Shizune noted that Konoha has yet to apply any genin of their own. This resulted in Tsunade needed to even more paperwork than normal, much to her dismay. Later, when Tsunade heard that Sakura was personally handling an operation for a severely injured man, Tsunade was worried about Sakura and went to watch. Upon arriving, she caught Sakura in time as she overtaxed herself from the procedure, but not without successfully healing the man. As Sakura was resting in Tsunade's hold, the Sannin congratulated Sakura for how far she has come.

When approached by Kankurō, he tells her of the proposal of letting Sunagakure personally take charge of the second round as they are more familiar with their territory. Sceptical at first, she asks for additional reasons, ultimately allowing them the privilege, but not before stating that the jōnin of the genin teams will still have to follow up with their team to Sunagakure. Later, Kakashi returns from his mission to report his failure at learning anything useful about Amegakure. He also noted that despite his seamless and stealthy re-entrance to the village, he was almost immediately pursued, forcing Kakashi to retreat out of the village. As Kakashi noted that with how the pursuers only knew of his general location and not that it was actually him, he concluded it was as if a ghost was watching, further troubling Tsunade. Later, Tsunade sent word to Konoha-nin in Sunagakure who were proctoring the exams to be on guard for anyone attempting to kill Gaara with new evidence showing that there were still many against Gaara being Kazekage.

Part II
During the time-skip, Tsunade continued her duties as Hokage and her tutelage of Sakura as a field medical-nin. Also during this time, the Hokage Monument was altered to include Tsunade's face in chronological order.

Kazekage Rescue Mission
While taking care of reports for genin missions, Tsunade learned that Jiraiya and Naruto had returned. Tsunade then decided to test Naruto's, as well as the now chūnin Sakura's, growth as ninja by pitting them against their former jōnin-sensei Kakashi. After the two succeeded in their challenge and received praise from Kakashi, Tsunade officially made them a unit under their old name "Team Kakashi".

Later, while deciding on Team Kakashi's first mission, Tsunade received word from Sunagakure that the Akatsuki had abducted Gaara, now the Fifth Kazekage. Out of respect for the Konoha-Suna alliance, Tsunade sent Team Kakashi to assist. A few days later, Tsunade had a bad premonition when she discovered she won a major sweepstakes and sent Team Guy as backup for the mission in response.

Tenchi Bridge Reconnaissance Mission
After Team Kakashi and Team Guy returned from rescuing Gaara, Tsunade was informed that the fallen Akatsuki member Sasori had intended to meet an agent of his working within Orochimaru's ranks. Seeing the chance to get intelligence on Orochimaru, Tsunade decided to have Team Kakashi capture this spy. Unfortunately, the elders were against letting Naruto go out on dangerous missions as the Akatsuki sought to capture him. Tsunade sternly voiced her belief in Naruto. The elders ultimately yielded under the condition that Tsunade added one of the men of Danzō Shimura, Hiruzen's fierce rival and leader of the Anbu Root division, to Team Kakashi. With Kakashi currently hospitalised, Tsunade also added an Anbu agent codenamed "Yamato", mainly for his ability to utilise the Wood Release and its ability to suppress the tailed beasts, should Naruto get out of control. She also warned Yamato to keep an eye on Danzō's addition to the team, Sai.

After Team Yamato returned, having failed their mission but gained new information on Sasuke, Tsunade surmised that Sasuke's immense growth may have come from the assistance of Orochimaru's use of kinjutsu and Kabuto's medical ninjutsu. Tsunade was also troubled to learn that Danzō, in his self-righteous ideals, was willing to give the enemy top-secret information in an effort to complete the mission as Sai was instructed to give Orochimaru Anbu data should they meet.

Twelve Guardian Ninja
In the anime, word reached Konoha that several villages on the Fire Country's borders were being attacked. Tsunade sent several teams to investigate. She also sent Team Yamato to investigate several tombs near the Fire Temple being disturbed. When Team Yamato returned, they informed Tsunade that the tombrobbers were apparently after corpses of four former members of the Twelve Guardian Ninja. Team Yamato also brought an unofficial new member to the team from the Fire Temple to replace an injured Sai, a young monk named Sora. Tsunade also received a message explaining Sora's troubled past and unusual powers that he is not able to control that lead to great damage of the Fire Temple.

Later, Tsunade had the Anbu apprehend Danzō due to his recent and possibly treacherous actions and ninja from the Amegakure with Danzō. Before she could interrogate the man, the elders arrived. They revealed that the Rain ninja was a double-agent working for them. The elders explained the same tomb-robbers Team Yamato encountered may also be after Sora. The elders and Danzō came to the conclusion they should confine or eliminate him. Before Tsunade could voice her refusal, Sora was found spying on them. Convinced that Tsunade wanted to eliminate him, Sora became furious at her. Sora then asked Asuma if it was true that Asuma killed his father Kazuma. When Asuma sadly admitted it, Sora's rage unleashed his hidden powers and was able to escape.

Later while Tsunade was deciding what to do about Sora, the village had a complete power-outage, thanks to the tomb-robbers. They arrived in the village and surrounded it in a giant barrier. They voiced their disdain for Konoha as they viewed as an imbalance to the Fire Country's power and sought to destroy the village. As they overwhelmed Konoha's forces with a zombie resurrection technique due to most of the ninja being outside the village, Tsunade discussed the situation with Shikamaru. It was determined through Asuma that the tomb-robbers intended to destroy the village with the deadly Limelight technique through the four resurrected guardians.

After the tomb-robbers were defeated and Sora was purged of his powers, Tsunade forgave Sora for his mistakes and was allowed to leave the village in peace.

Akatsuki Suppression Mission
Later, when two Akatsuki members entered the Land of Fire — namely Hidan and Kakuzu — Tsunade mobilised the Nijū Shōtai to look for and if possible, capture the Akatsuki duo. While capture never came to be possible, the Akatsuki members were both defeated. Tsunade later performed an autopsy on Kakuzu, and found Naruto's newest technique, Wind Release: Rasenshuriken to be too dangerous for use, based on the damage done to Kakuzu's body and Naruto's arm. She explained that the attack had struck at a cellular level, causing extensive damage to the both of them, and regretfully told Kakashi and Yamato not to allow Naruto to use the technique again.

Three-Tails' Appearance
In the anime, after finishing her autopsy on Kakuzu, Tsunade received a report from a deceased Anbu captain about Orochimaru and Sasuke's whereabouts. She called for Kakashi, and put him in charge of Team 8 to investigate. Because the mission involved a chance of finding Sasuke, Tsunade tried to keep Naruto from finding out about it. He found out anyway, so Tsunade didn't hesitate to send him as back-up.

Later, Tsunade received news that Team Kakashi had encountered the Three-Tails. Deciding that they needed to capture the beast quickly, as to not let it fall into enemy hands, Tsunade ordered Tenten, Rock Lee, and Ino Yamanaka to aid Team Kakashi in sealing the beast. Before sending them out, Tsunade made a large and special scroll to aid the team in sealing the beast. She also decided to summon and send out Katsuyu for further assistance. When the forces they sent continued to have problems with the sealing, Tsunade called them back to Konoha, and sent some Anbu to replace them. After she heard about the Anbu losing contact with Konoha, and the disappearance of the Three-Tails, Tsunade suspected that Akatsuki were somehow involved.

Itachi Pursuit Mission
Tsunade assigned Team Kakashi and Team Kurenai on a mission to find Itachi Uchiha in the hopes that it would lead them to Sasuke. Jiraiya later comes to inform her that he had found the location of the leader of Akatsuki. Despite her insistence for his location to formulate a surprise attack, Jiraiya instead invites Tsunade for drinks, which she ultimately ends up agreeing to it. While in Shushuya, Jiraiya reveals the details of the Akatsuki's leader and that he was in Amegakure and the difficulty of getting into the village. As Jiraiya declares that he would infiltrate the village on his own, Tsunade objects but Jiraiya reminds her that he is one of the Legendary Sannin and what that meant. After the two reminisce a bit, Tsunade tells Jiraiya to come back alive and if he needed help to send a toad and she'd come in person to back him up. On departing, Jiraiya tells her to remain cautious of Root.

Six-Tails Unleashed
In the anime, word reaches Konoha that the Tsuchigumo clan's fort protecting a powerful forbidden technique was under attack. With Team Kakashi and Team Kurenai being the closest, Tsunade sent Katsuyu to inform them of their mission to aid the Tsuchigumo clan, in accordance with the peace treaty the Third Hokage made with them. Tsunade later receives word from the teams that they and the clan have considered destroying the technique to end the possible danger it can cause.

Pain's Assault
When word reaches Konoha of Jiraiya's death, Tsunade makes the village's top priority to analyse the clues Jiraiya gave them to uncover Pain's identity. While the likes of Shizune, Ibiki, and Shikamaru are hard at work, Tsunade allows herself an opportunity to cry for her old friend, remembering all the memories they had share in their youth. Naruto, just as badly affected by Jiraiya's death as Tsunade, went away to train, both of them knowing that he was Pain's next target.

When Pain's assault on Konoha began, Tsunade tried to send word for Naruto to return home. She was stopped by the Konoha Council, who feared his capture by the Akatsuki. However, Tsunade insisted that they must have faith in Naruto, along with the rest of the next generation, and so they relented. Tsunade began issuing orders for the village's defence, placing extra protection around those still working on Pain's secret. She summoned Katsuyu, and had her divide and seek out every villager so that she could protect and heal them remotely. While sitting in the middle of a seal guarded by Anbu, transferring her chakra to Katsuyu, she was found by Pain's Deva Path, whom she recognised as one of the orphans Jiraiya had trained in the past. Tsunade refused to tell it where Naruto was, proclaiming that Akatsuki was just a terrorist group and that Konoha would not give in to their demands. Despite this Pain discovered Naruto's location through other means, the Deva Path resolved to make Tsunade see what Akatsuki's true goals were, by witnessing peace.

When the Deva Path jumped into their air, Tsunade and her Anbu followed only for the village to be destroyed. In the few moments between when the destruction began and ended, Tsunade poured all her chakra into Katsuyu in order to keep the villagers safe. In the aftermath, she confronted Pain, who attempted to kill her with his Asura Path. It was stopped by Naruto, who informed Tsunade that he would personally deal with Pain. Leaving a clone of Katsuyu with Naruto, Gamakichi carries Tsunade to Sakura. Having used up almost all of her chakra, Tsunade's elderly form resurfaced, she then falls into a coma and does not see Naruto's victory over Pain.

Fourth Shinobi World War: Countdown
While Tsunade remained in a comatose state, Danzō Shimura was chosen to replace her as the Candidate Sixth Hokage. However, he was killed by the now-international criminal Sasuke Uchiha after the Kage Summit and the village prepared to make Kakashi Hatake the new Hokage, but Tsunade woke up before the appointment could be finalised. Tsunade learned of everything that happened while she was in her coma; the start of the Fourth Shinobi World War, the Shinobi Alliance, and the "identity" of Tobi. After replenishing her chakra levels, she convened a war council to prepare the village for the impending war. In the anime after the war council, she calls a private meeting in her temporary office as they discuss the impending war.

Three days later, Tsunade goes to Kumogakure to meet with the other heads of the Alliance. She is warmly greeted by the Fifth Mizukage while the Third Tsuchikage suggests she retire so that she can finish recuperating. When they get down to business, Tsunade learns that the other Kage have decided to send Naruto and Killer B into hiding to keep them safe from Akatsuki. Tsunade argues against this, believing that the jinchūriki will be valuable assets in the coming war. The other Kage insist that it's for the best and the Fifth Kazekage reminds her that she must also take others' views into consideration. She eventually agrees with their decision, albeit reluctantly. Later, she helps organise the joint armies, placing particular interest in the Logistical Support and Medical Division and the Intelligence Division. In the anime after the meeting with the other heads of the Alliance she requests the Fourth Raikage that B teaches Naruto to achieve the control over the Nine-Tails.

Power
In the anime, Tsunade tasked Team Kakashi with the mission to investigate the massacre of the Tonika Village. She noted that she wished that she could send more persons along with them, but currently they were elsewhere investigating a grave robbery and the theft of Hidan's Triple-Bladed Scythe from the Nara clan's forest. She later showed Kakashi Hatake, Might Guy and Shikamaru Nara the results of Team Kakashi's observations and sends them out to assist them.

Fourth Shinobi World War: Confrontation
Later, Tsunade remained at headquarters with the Raikage and the Tsuchikage, providing input when needed. When the First Division engaged several reincarnated ninja, Tsunade was disturbed by the possibility that Dan may be amongst their numbers. She is later surprised by news that enemies on the battlefield contained the Nine-Tails' chakra.

When more news reached headquarters of Naruto and B's escape from their confinement, the Raikage asked Tsunade to help him deal with them. She summoned Katsuyu and leaves a clone at headquarters, taking another Katsuyu with her so that they could keep up-to-date on any urgent matters at headquarters. When they intercepted Naruto and B, Tsunade was amazed by Naruto's subjugation of the beast. Naruto appealed to Tsunade to let him and B pass, but she informed him that she could no longer act independently, and must do what was best for the Alliance. Naruto tries to escape but was stopped by the enraged Raikage, who voiced his willingness to kill Naruto and B if they would not submit. Upon hearing this however, a shocked Tsunade, told him that she would not allow him to do any such thing.

Turning to oppose the Raikage instead, she remembered Naruto's words, that he would not die until he became the Hokage, and argued that even if Naruto being killed delayed the enemy's plan, that it was unlikely that another jinchūriki would have the same success as Naruto had with controlling the Nine-Tails, and going against A's instructions, she would allow them to enter the battlefield. When despite this it seemed as though A would not be swayed, Tsunade was intent on fighting him, but, as it turned out, A was testing Naruto one final time and then agreed to let him and B continue on to the battlefield when the young man proved himself.

Upon returning to headquarters, Tsunade reviewed the data from the Logistical Support and Medical Division autopsy and was disconcerted by what Madara Uchiha and Orochimaru had done with her grandfather's DNA, and concluded that harvesting the cells was probably what had allowed Madara to live for so long. When A asked if there were any hints on how to defeat Madara, Tsunade replied saying that Madara may in fact be the true definition of the word "immortal". She then told Shikaku to inform Naruto and B about the White Zetsu Army clone's transformation ability.

Fourth Shinobi World War: Climax
Having heard a report from Inoichi about the progress that the Alliance was making on the battlefield after Naruto's release, Shikaku commented that they were gaining the upper hand. At this, Tsunade smiled at A triumphantly. They are subsequently told, however, that a new chakra had been sensed in the region of the Fourth Division. This was confirmed to be the real Madara Uchiha which sent those at headquarters into confusion. Mabui inquired about the reason behind the masked man assuming the name "Madara", to which Tsunade responded that, even more than a name, Madara was an ideal which struck fear into people from just the simple idea of him. A sudden tremor was felt, and after hearing the report from Inoichi that a meteorite had been dropped on the Fourth Division, and hearing Ao report that the lives of several shinobi had been lost, Tsunade decided to head out to the front-lines of the battlefield personally.

Adamant about her decision, she told Mabui to prepare her Heavenly Transfer Technique to transport her there. Mabui protests however, saying that her technique was not intended for use on living organisms. She comments that only the Third Raikage could withstand her technique because of his special body. Shikaku also tried to dissuade Tsunade, telling her it was a huge gamble regardless, and reminded her that she wasn't so lucky when it came to gambling, so they should have the Hokage Guard Platoon use the Flying Thunder God Technique to transport her instead.

Though she admits that she is bad at betting money, she argued that it was a different matter when it came to her life, citing that as the reason why she's still alive. She also claimed they should use the Flying Thunder God Technique to transport Mei, since they needed a way to deal with Madara's Fire Release techniques, and that she would simply use her Strength of a Hundred Seal to heal any damage. Despite Mabui's insistence, A told her to prepare the technique for two, as he would be accompanying Tsunade. Mabui eventually conceded to the order, and used her technique to send them to the battlefield. Upon their arrival, Tsunade attacked Madara immediately with a kick sending him flying while A attacked Mū. Sustaining some minor injuries in transit, she released the seal on her forehead and used her Creation Rebirth technique to heal herself. She stood alongside all the other Kage as they prepared to fight Madara.

As the battle with Madara began, Tsunade began healing Ōnoki and Gaara's injuries first while Mei and A held off Madara. Naruto questioned Tsunade on why she hadn't collapsed after using Creation Rebirth when she arrived, to which she responded that this instance was different from what she used during Pain's invasion, as this time she was only healing her own injuries which weren't as bad as they were back then. Naruto asked to be healed despite being a clone, so he could join the battle as well, but Tsunade and Ōnoki stated there was no need, and that the war was no longer just about protecting him. After being completely healed, Ōnoki and Gaara joined the battle just in time to protect everyone from Madara's attack. As Madara is pushed back by the Kage's combined assault, Naruto turned to Tsunade, but was told by Ōnoki that this battle is no longer Naruto's to fight. Tsunade told Naruto that they could only win if they defeat both Madaras — stating that while they protected him from the reincarnated Madara on this side, he needed to protect them from Tobi. Before Naruto's clone dispersed, Tsunade and the other Kage left him with one final word: "win."

As the battle continued, Tsunade took up a supplementary role and hung behind the main battle to heal the other Kage whenever they got injured. As Madara used the Wood Release: Advent of a World of Flowering Trees technique, Tsunade was visibly shocked to see him use her grandfather's technique before calling out to Gaara, who suspended them above the attack. She then told the other Kage to ensure they didn't inhale any of the pollen, but they were ambushed and knocked back to the forest floor by Madara's Susanoo. Inhaling the pollen, they fell unconscious until Ōnoki managed to destroy the trees and part of Madara. Tsunade later stared in shock as she sees the face formed from her grandfather's DNA jutting out of Madara's now-exposed chest.

A regenerating Madara asked Tsunade if she was a descendant of the man on his chest. After this was confirmed, he declared that she would be the first to die. As Mei stated that attacking the medical-nin in a team was a common tactic that they'd never allow, Madara said he was targeting Tsunade not because she was a medic, but because she was a Senju descendant whom he has deemed to be weak compared to her grandfather. After Madara recounted Hashirama's superior skill in medical ninjutsu to that of Tsunade, who could not use Wood Release, she admitted that while some of those things were true, he was wrong in thinking that she was a weak woman who inherited nothing from her grandfather. She states that she inherited something more than simple power: the Will of Fire, which Madara should not take so lightly.

As she denounced Madara's claims, she told him of the four rules she created for her students and medical-nin alike stating that she was the only one who was allowed to break these because of rule number four: only those that had mastered the Creation Rebirth technique were allowed to break the other three rules and engage directly in battle. With this she completely released her Strength of a Hundred Seal, activated the Ninja Art Creation Rebirth — Strength of a Hundred Technique, and confronted Madara — cracking his Susanoo's ribcage with a single punch. As Madara counter-attacked with the Fire Release: Great Fire Destruction technique, Mei intercepted this and sent Madara flying into the air with some of her Water Release techniques. With this, A, Ōnoki and Tsunade prepared a twofold attack which sent Madara plummeting into the ground. Barely giving him time to relent, Tsunade chided him again about inheriting the Will of Fire as opposed to something physical wondering whether or not he was even listening.

Attacking once again, Tsunade was able to land a blow to Madara directly which destroyed his entire right side. Seemingly incapacitated, Gaara bound and sealed Madara. As Tsunade congratulates the other Kage, her face widened in shock as one of Madara's Susanoo Swords emerge from the ground and impaled her. As Madara emerges from a root, he revealed that what they had sealed was nothing but a mere wood clone and that when Hashirama used it during their battles, he was the only one that was able to distinguish the clone with the use of his dōjutsu.

Just as Madara sets his sights on the other Kage — believing her to be dead — Tsunade broke the sword lodged in her abdomen and, in one fluid motion, swung it at him, but Madara managed to block it by using his Susanoo's ribcage. Tsunade was then sent flying back when Madara attacks her — crashing into a wall. She emerged seemingly unaffected by his attack as her wound heals. Madara praised her for this, and compared her technique to Hashirama's, though she admitted that she had just intended to create an opening for an attack. Jeering Madara, Tsunade stated that it was true that he was able to outwit them with his wood clone, but, that at the same time it could be said that they had cornered him into using the clone. This causes Madara to use the Multiple Wood Release Clone Technique, sending five clones to fight each of the Kage. With this he asks them whether or not they'd prefer the clones use Susanoo, much to the Kage's collective shock.

As the battle raged on, Tsunade sent one of the Susanoo-clad clones plummeting into the ground. After A berated her increasingly reckless actions Tsunade reminded him that she had already stated she would bet her life and removed the two broken Susanoo blades from her abdomen. This however, caused her some pain and she coughed up blood. Spurred on to stand and fight by Ōnoki once more, the five Kage regroup and launch a new strategy with Tsunade transferring some of her chakra to Ōnoki in order to facilitate his large-scale Dust Release technique, taking out all twenty-five clones in one shot. After a follow-up combo attack from A, Mei, and Gaara, Madara acknowledges that they are indeed worthy of their Kage titles, and manifests his complete Susanoo. After Susanoo is completed, Tsunade along with the other Kage stared in shock at the humongous construct. Now realising the difference in power between the Kage and Madara, Tsunade wondered whether her grandfather really fought and defeated someone like that before being knocked down by a swing of Madara Susanoo's sword. As they regained their footing, she and the other Kage stood to face Madara once more. As Madara prepared to deliver another devastating blow with his sword, Tsunade formed a seal, seemingly prepared to counter the attack. However, Madara's attack is halted as he was then enveloped by a light of sorts and it appeared as though he was about to be released. She wonders who could possibly have stopped the Impure World Reincarnation since the Alliance was still in the process of searching for Kabuto.

Ōnoki cautioned his fellow Kage as Madara made a last desperate attempt to attack them, using the Fire Release: Dragon Flame Release Song Technique. Intercepting the attack, Tsunade dissipated the flame dragons with her bare hands. Her arms are burned in the process, and though Ninja Art Creation Rebirth — Strength of a Hundred Technique was able to repair the damage, the technique wore off shortly afterwards and her Strength of a Hundred Seal disappeared as her chakra reserves depleted. As she began to lose consciousness while still in mid-air, Madara prepared to impale her with his Susanoo's sword once again, but Tsunade miraculously dodged the blow. As she wondered what it was that saved her, she heard a voice inside her subconscious where she saw Dan standing before her. He commented that she hadn't changed since he was alive, still taking risks in combat, but then thanked her for achieving what he didn't by becoming Hokage and apologises for bringing so much pain into her life with his death. He stated that he would be waiting for her on the other side, but insisted that she not come too soon, as she was his dream itself. He left her with a kiss on her forehead, reminiscent of the one she gave him decades before, grateful that he was able to protect her, even if it meant being used in the Impure World Reincarnation. Before departing, he gave her the remainder of his chakra and as the Strength of a Hundred Seal reformed, Madara commented that she has regained her vitality and wondered how that could be, to which she simply replied saying she had met an old friend. With Madara having broken the Impure World Reincarnation technique's contract with the summoner, however, the Kage now faced an opponent with limitless chakra, and an immortal, uncontrolled body.

Despite the Kage's attempts to stop Madara, they ultimately failed and were left heavily wounded, with Tsunade bisected. Despite her condition, Tsunade was able to muster enough energy to summon Katsuyu. Distressed by its master's condition, the slug immediately stated that it would put her back together. Tsunade instead asked Katsuyu to first bring the heavily injured Kage to her, stating that she would save them first before healing herself. Later, she was approached by a revived Orochimaru, who remarks about her current state. He was joined by Karin and Suigetsu Hōzuki. Orochimaru ordered Suigetsu to aid Katsuyu in re-attaching Tsunade's bisected body. Meanwhile, Karin allowed Tsunade to bite down on her arm in order to heal her wounds. After she'd recovered, Tsunade thanked Orochimaru and reluctantly admitted that he seemed to have changed since being sealed by Itachi, though she also noted that had he changed earlier, Jiraiya might have still been alive.

Just before they parted ways, Tsunade was shocked to find out that Katsuyu's other half was already on the battlefield, and she could in fact update them on the situation there. Tsunade fully healed her fellow Kage, and the group prepared to head back to the battlefield as soon as possible. Atop Gaara's sand, the Kage make their way to the battlefield.

Birth of the Ten-Tails' Jinchūriki
Upon seeing the enormous tree ahead of them, Tsunade inquired to Katsuyu about the current situation. While making their way there, Tsunade and the others are startled when a telepathic link was opened and she heard the voice of her grandfather who warmly greeted her. Through this method, she listened on as her grandfather explained the situation and what Madara's intentions were. Later, As Naruto's anger at the loss of his comrades he had fought so hard to protect grew, his emotions and memories were conveyed to everyone within the telepathic link. Tsunade sympathised with Naruto over the loss of Jiraiya and later viewed her grandfather's memories of the first ever Summit of the five Kage before arriving on the battlefield as Hashirama declared his wishes for the future of the world.

Noting that they needed to disperse across the battlefield immediately to keep the morale going, Tsunade's first act was to head over to where a chakra-depleted Shikamaru was and expedite his healing before commending Sakura for a job well done. Heading over to her grandfather, she apologised to him for the state of things, she then told him that he himself had no need to apologise either as it was not only the ills of the past that got carried into this generation, but good things such as his indomitable Will of Fire. With this, she called out to her troops to prepare to fight.

As the troops around her charged forward, she and Sakura remained behind. Releasing their Strength of a Hundred Seals, Tsunade noted that with two of them able to use the seal they would be able to summon one tenth of Katsuyu's main body from the Shikkotsu Forest. As the slug appeared on the battlefield and began to deconstruct, Tsunade noted that they could use Katsuyu's body in this form to create a recovery area where the shinobi could heal themselves and continue fighting.

The Alliance is successful in defeating Obito, but as they charged forward to finish the Uchiha, Tsunade stopped them after seeing Minato and Kakashi with him. They soon realise that the war was not yet won after Madara Uchiha is revived. Their battlefield is soon assaulted by Tobi's statue. As Tsunade wondered who was using the technique, Gaara arrived with Naruto in tow pleading with Tsunade and her students to help him, however, Tsunade noted that she and Shizune no longer had enough chakra to use medical ninjutsu and directed Sakura who still had barely enough to help.

After their enemy stopped the battle abruptly, Tsunade watched on alongside her sensei as Madara's dōjutsu was reflected on the moon, ultimately also falling prey to the technique. Inside of it, Tsunade dreamed of a happy life with Dan still alive and as the Hokage, along with Nawaki, Jiraiya, and Orochimaru a part of it, although she wasn't amused of Jiraiya's attempt to influence Nawaki to read his Icha Icha novel when she caught him.

Kaguya Ōtsutsuki Strikes
After the Infinite Tsukuyomi was dispelled, Tsunade would retire from her role as Hokage, giving the position to Kakashi.

Kakashi Hiden: Lightning in the Icy Sky
Tsunade makes an appearance in this novel.

The Last: Naruto the Movie
Two years after the Fourth Shinobi World War, Tsunade assisted hundreds of Konoha citizens in evacuating to an underground shelter to protect them from falling meteors. Afterwards, she attended Naruto and Hinata's wedding and congratulated them.

Sakura Hiden: Thoughts of Love, Riding Upon a Spring Breeze
Tsunade makes an appearance in this novel.

Epilogue
Years later, Tsunade crafts for both Naruto and Sasuke prosthetic arms from the cells of her grandfather, Hashirama, and attends an ex-Kage meeting with the other former Kage at the Tsuchikage residence, where the Tsuchikage now resides due to his advanced age.

Naruto Shippūden the Movie
Tsunade sent out many advance teams to stall the stone army. Naruto Uzumaki, Sakura Haruno, Neji Hyūga and Rock Lee were sent to guard Shion, and deliver her to the shrine where Mōryō's body was sealed.

Naruto Shippūden the Movie: The Will of Fire
Tsunade was reported by Kakashi about the mission, while worrying that the next ninja targeted will be him. Tsunade seems to not care so much, telling Kakashi to relax. At the hospital, Kakashi gives Naruto his bells, which they used for their first drill together, and tells him to fix them because he crushed them. Tsunade sent Konoha Anbu to Mount Shumisen to search the area for tracks of the missing kekkei genkai ninja. Tsunade is awaiting Gaara at a secret meeting place to discuss what shall be done. However, on the way there Gaara and his Sunagakure shinobi are attacked by a hawk, which traps them in an avalanche.

Naruto the Movie: Blood Prison
Tsunade states that Naruto is wanted for attempting to assassinate the leader of Kumogakure, the Raikage, and killing jōnin from Kirigakure and Iwagakure to Team Kakashi placed him under arrest and taken to the Hōzuki Castle, a criminal containment facility, also known as the "Blood Prison", in Kusagakure. She and all his friends have gathered there. Tsunade reveals that it was Naruto's mission to destroy the box and that no one believed that Naruto really committed any of the crimes.

Road to Ninja: Naruto the Movie
The alternate world's Tsunade, like the Tsunade that Naruto and Sakura know, is the Fifth Hokage. However, in compared to her other self, the alternate Tsunade wears glasses and is flat-chested. During her time in Konoha, the alternate Sakura nearly gets herself killed when pointing out Tsunade's busty appearance.

Creation and Conception
Tsunade's name is taken from the character of the same name from. The Tsunade in that story is vastly different in terms of personality, along with the fact that unlike her manga counterpart the original Tsunade was married to Jiraiya, however both were known to greatly excel in slug magic.

Trivia

 * means "mooring rope", which is not dissimilar to her brother's name, Nawaki, which means "rope tree". A similar word, could also be a play on Tsunade's personality.
 * In Naruto episode 72, Tsunade was seen in Hiruzen's flashback, however, her official debut was in Naruto episode 83.
 * Tsunade shares the same blood type with her former team-mates, Jiraiya and Orochimaru.
 * Tsunade was the first female Hokage, as well as the first female Kage, that appeared in the series.
 * Tsunade is first mentioned when Might Guy questions Rock Lee, Neji, and Tenten about their goals as genin. Tenten says that she wants to become a great kunoichi and follow the footsteps of the legendary Tsunade. She also made a cameo appearance in the Third Hokage's flashback during his time training the Sannin.
 * Studio Pierrot's Settei sheets of Tsunade show that she was 145 cm when she was part of Hiruzen's genin team, and that her high-heeled sandals she currently wears add 5 cm on to her height.
 * According to the databook(s):
 * Tsunade's hobby is gambling.
 * Tsunade wishes to fight Naruto Uzumaki.
 * Tsunade's favourite foods are chicken breast and sake, while her least favourite food is liver sashimi.
 * Tsunade has completed 1,256 official missions in total: 40 D-rank, 236 C-rank, 467 B-rank, 418 A-rank, 95 S-rank.
 * Tsunade's favourite phrase is, referring to getting rich without much effort.
 * While Tsunade's English anime voice actor is Debi Mae West, in some games she is voiced by Mary Elizabeth McGlynn, who is Kurenai Yūhi's voice actor. In Naruto: Clash of Ninja Revolution 2, while being voiced by Mary Elizabeth McGlynn throughout the story-line, during game-play, most of Debi Mae West's voice-overs from the first game are still used.

Quotes

 * (When about to fight Naruto) "One of the Legendary Sannin taking on a snot-nosed genin… I oughta be ashamed of myself."
 * (To Jiraiya about Naruto) "Jiraiya, are you the one who taught him the Rasengan? Are you acting like a teacher by teaching him something he can't master? Don't give him any ideas! That's why this kid likes to daydream that he's going to become Hokage someday."
 * (To an unconscious Naruto) "It's because to be Hokage… is your dream… isn't it Naruto? One last time… just one last time… I place the odds on you."
 * (To Orochimaru) "From now on… I too shall bet my life!"
 * (To Orochimaru) "Why am I putting my life on the line? Because now… I am the Fifth Hokage of Konohagakure!"
 * (To Shikamaru) "Grow up… Death comes with being a shinobi… There are times when death is hard to accept, but if you don't get over it, there's no future…"
 * (To the advisers, Konoha Council members) "People like Jiraiya… and Sarutobi, and Elder Chiyo of Suna possessed something you two sorely lack. Do you know what that is!? …Faith! My grandfather, the First Hokage, believed in you and entrusted you with the village. Now it's your turn to believe in these children and entrust it to them!"
 * (To Pain) "I am the Fifth Hokage… You've trampled on our ancestors' treasure… their dream… And you will pay the price! As the Hokage, I will put a stop to you here and now!"
 * (To Shizune) "People become stronger because there are memories that they will not forget."
 * (About her bad gambling) "Only when it comes to money. My life is a different story. I'm still alive aren't I…?"
 * (To Madara) "Although I am a descendant of the First Hokage, it's true that I don't know how to use Wood Release. And compared to him, who was able to use medical ninjutsu without even making seals, it's true that my own ninjutsu is nothing to brag about. And it's true that I'm a woman… but I'm definitely not a weak woman… What I inherited from my grandfather isn't just simple 'power'. My true strength comes from that which was passed down from the First to each generation afterwards… Don't underestimate the Will of Fire!"