As a child, he was born into the Estraneo family where experiments were performed on him regularly. This led Mukuro to develop a hatred of the mafia. Eventually he killed his captors and persuaded Ken Joshima and Chikusa Kakimoto to follow him as they had also been experimented on.
Some time later, Mukuro had been adopted by a mafia family. However, he possessed a member named Lanchia and killed the family he had been adopted by. Mukuro would then go on to use Lanchia to kill more mafia families and as a decoy. Mukuro and his two followers were eventually imprisoned in Vindice, which is reserved for the most dangerous mafia criminals.
Mukuro, Ken, Chikusa and others that he recruited escaped from Vindice to enroll in Kokuyo Middle School. Mukuro then kidnapped Fuuta to draw out the Vongola Tenth and defeated Kyouya Hibari using his weakness to cherry blossoms. Tsuna eventually confronts Mukuro and Mukuro revealed he planned on possessing Tsuna to get revenge against the mafia. Mukuro and his followers were defeated and sent back to Vindice.
Mukuro, Ken and Chikusa attempted another jail break which resulted in Mukuro giving himself up so the others could escape. He then came into contact with a girl named Nagi who was on the verge of dying. She could sense him so he agreed to give illusionary organs in return for her acting as a vessel for him. He renamed her Chrome Dokuro and agreed to be Tsuna's Mist Guardian in exchange for his followers freedom.
During the Mist Ring Battle against the Varia, Chrome was injured in her fight with Mammon and Mukuro showed up to defeat him. Mukuro then asked Lanchia to help the Vongola because he knew of Xanxus's plans.
In the Future Arc, a member of the Millefiore Family claimed to have defeated him once before. He attacked Chrome in the future but Mukuro had possessed his box weapon. Mukuro then defeated him with Chrome's help. It is then revealed that Mukuro had possessed a member of the Millefiore Family and the boss Byakuran seemingly defeated him in battle. He did manage to send Chrome and Tsuna a message in their dreams about Shouichi Irie's round device.
Tsuna and the others came back to the past for the Arcobaleno Trials. Mukuro contacted Chrome and noticed that she appeared to have been through an ordeal. He then said that he would let her keep it secret and says he will stay by her side no matter what happens. When Colonello's trial finished Mammon who impersonated Tsuna yelled at Chrome causing Mukuro to appear because he was angry at her being harassed. Mammon then tricked him into coming outside where he fought with Hibari. Tsuna was able to stop the two of them from fighting.
Mukuro then asked Tsuna not to drag Chrome far from his reach before disappearing again. When they travel back to the future and Byakuran challenges the Vongola to a game of Choice, Mukuro creates a real illusion of himself allowing them to escape before it is destroyed. In the past again, when Tsuna is fighting Daemon Spade he fires an X-Burner not knowing it was really Kyoko and Haru. Mukuro possessed Chrome and then saved them. He then gets angry at Daemon for torturing Chrome and says he will let Tsuna deal with him instead. Daemon referred to Mukuro as the Mist Guardian which disagreed with because it was not his choice to do so. Daemon then asked him why he saved the girls and said it was because Chrome would have been upset if he didn't. Mukuro then told Daemon he wanted to destroy the Mafia which caused Daemon to laugh. Daemon then deemed him worthy of his inheritance. Before releasing possession of Chrome's body, he told Tsuna to watch over her.
In the future, Mukuro was rescued from Vindice by his subordinates and able to help in battle against Byakuran and his followers by creating illusions of the Vongola members so they could see how the enemies's attacks worked. This worked and eventually the enemy was defeated. In the past, Mukuro was able to recieve the memories of his future self.
Later, Daemon appeared again possessing one of the Shimon Family members. He then kidnapped Chrome, brainwashed her and then broke his control on her telling Chrome he would use her as bait for Mukuro. Mukuro appeared and was furious with Daemon for endangering her life. The two of them fought each with Mukuro who appeared to be the victor. However it was revealed Daemon succesfully possessed Mukuro's body. This forced Mukuro to possess his box weapon. Aftter Daemon was defeated Mukuro was freed from the Vindice.
Mukuro then left Chrome a note in Kokuyo Land to get out while he headed to France to recruit Fran. Fran chose to leave with Mukuro's group and they returned to Kokuyo Land. He then agrees to be Verde's representative for the Representative Battle of the Rainbow. On the next day, he declared war against Tsuna but Tsuna refused to fight him. He then told Tsuna he detested Chrome and to look out for her.
Mukuro then sent an illusion of himself to Chrome to check on her health and realized that her condition worsened. He told Chrome to tell him everything about her state otherwise she would die. Later he discussed the battle results and praised Verde's machine. Fran interupted them and Mukuro punished him by having train harder. Mukuro then stated he wanted to use the machine on the second day of the battle.
On the second day of the battle, Mukuro and his subordinates attacked Reborn and Yuni's teams. He disguised as Kikyo and destroyed Zakuro's watch. Mukuro was then injured by Colonello's attack but protected his boss watch. He and Fran fled seeing no merit in hanging aroud.
A member of the Vindice appeared in Kokuyo Land attacking Mukuro with intent to kill forcing him to fight. He then left going somewhere else and encountered Tsuna, Reborn, Gokudera and Yamamato. He decides to fight them but stops when a Vindice appears to attack them. This leads Mukuro to declare a truce with Tsuna. Chrome arrived just in time when he and Tsuna were about to be defeated. He and Chrome then joined together creating an illusion powerful enough to defeat several Vindice. Mukuro and his subordinates then returned to Kokuyo Land to treat their injuries. He then meets at Tsuna's house where Tsuna asked everyone to help him in the battle.
After Bermuda and Jager recieved that info that decoy puppets of Team Verde were defeated they decided to go help the other members of the Vindice out. However, Mukuro and several of the other characters appeared to fight Bermuda and Jager so they could not assist their teamates.
Mukuro is a very powerful illusionist who is not fooled easily by other illusions. He is also shown to be capable of combat using his trident and if he scratches someone with it he can possess that person after shooting himself with a special bullet called the Posession Bullet. He can also manifest real illusions, summon deadly animals such as poisonous snakes and releasing his aura by stabbing himself in the eye which increases his combat ability.