Itachi was born into the Uchiha clan to Mikoto and Fugaku and was praised by all as the best of his generation; a genius above all others. Even by the standards of the battle-adept Uchiha clan, Itachi's prowess far outshone them. However, not even his family, friends, or teachers could understand him. When he was only four, Itachi had already witnessed countless lives lost due to the Third Shinobi World War, which emotionally traumatised him and turned him into a pacifist.
During the Nine-Tails' attack on Konoha, Itachi held his infant brother Sasuke and told him that he would protect him no matter what as well as wondering where his parents had gone.
At age 7, he graduated from the Ninja Academy at the top of his class after only one year, mastered the Sharingan at age eight, passed the Chūnin Exams at age 10, and became an ANBU Captain at age 13.
He was praised highly by his father, who saw the family's future in Itachi and hence inadvertently neglected his younger son. However, during this time Itachi showed great affection towards his little brother and even encouraged his father to come to the Academy enrolment ceremony for Sasuke, something their father had otherwise forgotten, by saying that he would not go to an important mission that would establish Itachi a place in the ANBU ranks, otherwise.
When the Uchiha clan began planning to overthrow Konoha, Itachi, as an ANBU, was tasked with spying on the village. Knowing that a coup d'état would only lead to another Ninja War; Itachi began spying on the Uchiha instead, passing on information to the Third Hokage and the other Konoha elders. During this time he began to act strangely, not attending the clan meetings, speaking out against the clan and becoming the prime suspect for the murder of his best friend Shisui Uchiha, who was drowned in the Naka River. In reality, Shisui had entrusted his remaining Mangekyō Sharingan to Itachi, the other having been taken by Danzō. Itachi assisted Shisui in making it seem that his eyes were destroyed. Due to this the clan lost hope in Itachi, and his father began shifting his focus to Sasuke instead. Meanwhile, the Third's attempts to negotiate a bloodless end to hostilities between the two parties were proving ineffective so, against the Third's wishes, Danzō Shimura and the Konoha Council ordered Itachi to wipe out the Uchiha clan.
Before the fateful night arrived, Itachi discovered the existence of Tobi, who was attempting to rekindle the flames of war in Konoha. In return for not attacking Konoha, Itachi offered to help Tobi claim vengeance against the Uchiha for turning their backs on him decades earlier; Tobi agreed. Itachi slaughtered his entire clan overnight, sparing only Sasuke, because he could not follow through with the orders to kill him. Instead, he made himself out as a villain, who had killed their innocent family only to test his abilities. He told Sasuke that he was not even worth killing. In addition, Itachi told him, "You've always wanted to surpass me. That's why I'm going to let you live… if you wish to kill me, then hate me, despise me… and by all means flee, cling to your wretched life". Itachi also revealed to Sasuke where the secret meeting place of the Uchiha was hidden, and suggested that Sasuke go there to learn what the true history and purpose of the Sharingan was. He told him that "to awaken the Mangekyō Sharingan", he "had to kill the person he was closest to", and that "when we battle, we should have the same eyes".
Sasuke managed to stand back up, awaken his Sharingan, and pursue Itachi. Upon reaching Itachi, he managed to knock off his forehead protector. Itachi shed a tear as he was picking up his forehead protector. He then proceeded to incapacitate Sasuke, who awoke in the hospital remembering only that which Itachi wanted him to. By doing all this, he wanted Sasuke to take vengeance on him and become a hero to Konoha, thus redeeming the Uchiha name. Hoping that his beloved little brother would someday be powerful enough to kill him, Itachi left the village as a traitor. According to Tobi, Itachi also had a lover, whom he killed during the Uchiha clan massacre.
Knowing that Konoha would still want to eliminate Sasuke, Itachi pleaded with the Third Hokage to keep Sasuke safe. He also threatened Danzō to not harm Sasuke or risk Itachi revealing everything he knew about Konoha's secrets to enemy countries. Sasuke's safety was therefore secured and Itachi returned to his original plan of becoming infamous for his slaughter of the Uchiha clan.
Itachi joined Akatsuki in order to keep an eye on the organisation, along with Tobi, in case either ever acted against Konoha, all the while planning for his death at Sasuke's hands. While he was a member of Akatsuki, Itachi was approached by Orochimaru, who tried to steal his body to gain the Sharingan. Itachi trapped him in a genjutsu and severed his left hand as punishment, forcing Orochimaru to flee the organisation. He was partnered with Kisame Hoshigaki, who he initially greeted with threats after the latter tried to intimidate him. However, they eventually became good partners for sharing the common bond of having betrayed the people closest to them. Sometime after joining Akatsuki and forcing Orochimaru to flee, Itachi helped recruit Deidara by beating him in battle using only genjutsu, to which Deidara swore vengeance against Itachi.
At some point in time, Itachi contracted a fatal illness. He kept himself alive through the intake of various medicines and sheer "willpower", in the hopes of living long enough to die by Sasuke's hands.
Knowing that his end was near, one of Itachi's shadow clones confronted Naruto, who was looking for Sasuke. Although he claimed he wished only to talk, Itachi was forced to defend himself against Naruto's attacks. After fending off Naruto, Itachi asked why he showed so much interest in Sasuke, a traitor to Konoha. Naruto replied that he was more of a brother to Sasuke than Itachi had ever been, and that he would do whatever it took to bring Sasuke home. This caused Itachi to give a small smile, followed up by asking if he would always feel that way, even if Sasuke attacked Konoha. Naruto replied only that, if that happened, he would stop Sasuke without killing him and protect the village. Content with this answer, Itachi gave some of his power to Naruto, by forcing him to swallow one of his crows, and hoped he would never have to use it.
After his business with Naruto was done, another of Itachi's shadow clones went to meet with Sasuke. Sasuke exhibited a dramatic improvement in his abilities during their confrontation, so Itachi agreed to have their final battle at the Uchiha Hideout. He waited there for Sasuke's arrival, instructing Kisame to not let the other members of Sasuke's team interfere with their combat. Itachi and Sasuke met face-to-face and, while exchanging genjutsu, had a conversation about the Uchiha, Madara Uchiha, and Itachi's "true" motives of wanting to take Sasuke's eyes. When Sasuke managed to escape Itachi's Tsukuyomi, the genjutsu battle ended and the ninjutsu battle began.
Itachi used Amaterasu, but Sasuke protected himself by shedding his skin, a technique he was able to use due to Orochimaru being sealed within him. Using the shed skin as a decoy, Sasuke went below and fired a Fire Release: Great Dragon Fire Technique at Itachi's direction above although he only managed to burn away one of Itachi's sleeves. Out of chakra, he told Itachi about his final jutsu that, like Amaterasu, is impossible to avoid. Sasuke then used his trump card, on Itachi, who got his Akatsuki cloak burned off as a result.
However, Itachi managed to survive by using Susanoo to defend himself. With Kirin having expended all of Sasuke's chakra, Orochimaru was able to assume control and violently appeared through his Eight Branches Technique. However, Itachi was easily able to cut off the seven snake heads, leaving only one behind whose mouth Orochimaru appeared out of and thanked Itachi for pushing Sasuke so far, in the process setting him free and allowing him to take control of Sasuke's body. Itachi, however, stabbed Orochimaru with the Totsuka sword to seal him away with Susanoo, thereby removing the cursed seal from Sasuke's body.
As Itachi began to weaken, thus weakening Susanoo, Sasuke saw an opportunity to strike, but in vain, as Susanoo was still able to protect Itachi. His last option gone, Sasuke was pushed against a wall and left helpless as Itachi walked up close to him and seemed to be reaching for Sasuke's eyes. However, he instead poked Sasuke's forehead and smiled before saying, "Forgive me Sasuke… …It ends with this."; this was a reference to Itachi constantly poking Sasuke on the head when they were younger. With that act, Itachi finally gave in to his fatal illness, which he had been using medication and sheer willpower to fend off, and died.