During the second part of the Chunin Exams, Orochimaru killed the members of Team Shiore and impersonated them so that he could infiltrate the Forest of Death. During a confrontation with Naruto, Sasuke, and Sakura, he sealed Naruto's Nine-Tailed Demon Fox chakra and branded Sasuke with his Cursed Seal of Heaven. Orochimaru was discovered by Anko, but the exams continued due to his threat of retaliation. His Genin team was sent to kill Sasuke, but the three were unaware that they were just measuring posts for Sasuke's power. They failed in their effort, as Sasuke proved compatible with the Cursed Seal and used its power to drive them off.
During the final round matches, Orochimaru disguised himself as the Fourth Kazekage so that he could sit next to the Third Hokage. When the invasion of Konoha began, this gave him an easy opportunity to capture his former master. He isolated the Third from the other Konoha ninja, and had the Sound Four erect a barrier to prevent any interference. The Third, regretting letting Orochimaru escape years earlier, agreed to battle. Exhilarated that he could finally fight his former teacher, Orochimaru used Impure World Resurrection to revive the First and Second Hokage to give Hiruzen the same feeling.
In his old age, the Third was little match for Orochimaru and two of the Hokages, something made all the more difficult when the Hokages regenerated from any damage they received. In the end, the Third decided to use the Dead Demon Consuming Seal to seal away the souls of the Hokages, before turning on Orochimaru. Sensing what was happening, Orochimaru stabbed the Third in the back with his Kusanagi Sword. Unconcerned with the wound, since he would die anyway, Hiruzen struggled to seal Orochimaru's soul as well, but after an hour only had the strength to seal his arms. To do what little he could, he robbed Orochimaru of the use of his arms, in turn taking away his ability to use jutsu. The Third died, and Orochimaru cursed him. Unable to proceed with his plans, Orochimaru and the invaders retreated. Afterwards, Sunagakure broke ties with Orochimaru, after discovering that he killed the Fourth Kazekage.
Later on in the series Orochimaru planned to have his condition healed by appealing to his old teammate, Tsunade, a legendary medical ninja. He offered to revive her brother and lover, in the hopes that it would persuade her to cooperate. Although it seemed as though he had succeeded at first, it turned out that Tsunade had actually intended to kill him rather than heal him, in order to prevent another attack on Konoha. Kabuto intervened before she could do so, and Orochimaru expressed disappointment in the betrayal, even going so far as to say that he "would have kept his promise". Kabuto engaged Tsunade in an attempt to capture her and force her to help, but Jiraiya and Naruto soon arrived to help her.
Orochimaru and Jiraiya (having earlier been drugged by Tsunade and thus unable to properly perform jutsu) faced off, but could do little to each other. Kabuto, meanwhile, dealt with Naruto and Tsunade. When Naruto defeated Kabuto, Orochimaru, concerned that Naruto and the demon fox might become a problem in the future, tried to kill him. Tsunade stopped him, having decided to become the Fifth Hokage, and teamed up with Jiraiya against Orochimaru. Despite summoning Manda, Orochimaru was defeated. Healing his arms no longer being an option, Orochimaru retreated with Kabuto, deciding it was time that he took a new host body.
Two and a half years later, Team Yamato, hoping to find Sasuke, learned of an opportunity to meet with a spy in Orochimaru's organization. Kabuto turned out to be this spy, having come to meet with Sasori, Orochimaru's former partner, who had been keeping tabs on Orochimaru. Yamato disguised himself as Sasori and met with Kabuto, but Orochimaru soon interrupted. Having switched sides, Kabuto attacked Sasori, finding it to be Yamato. He called the rest of his team for back up and they faced off with Orochimaru and Kabuto. Although he was surprised to see Yamato, a former test subject of his, he showed more interest in Naruto. He expressed interest in seeing if Naruto was as strong as "his Sasuke", angering Naruto into a three-tailed state.
In this form, Orochimaru was able to elude Naruto, finding the battle extremely enjoyable. When Naruto progressed to a four-tailed transformation, however, Orochimaru took the battle seriously, recognizing that Naruto's Four-Tailed Fox Menacing Ball could kill him. After evading the attack, he used his Kusanagi to force Naruto away while he collapsed, his body beginning to reject him. While he briefly recuperated, he was approached by Sai, who made an offer on behalf of Danzo to work together in destroying Konoha. Intrigued, Orochimaru and Kabuto took him back to their base.
Later, after the rest of Team Yamato arrived at the lair and Sai teamed up with them, Orochimaru confronted Sai and Naruto to question Sai about his loyalties. He fled before he could be drawn into another fight, and later kept Sasuke from killing the team, noting that they might kill another Akatsuki member like they had done with Sasori.
On the verge of being rejected by his current body, Orochimaru contemplated how best to take Sasuke's body. Also, in the anime only, he and Kabuto recapped all the events that led to Sasuke defecting, and how much he had improved since. Before he could formulate his plan, Sasuke attacked him, trying to kill him with Chidori Sharp Spear, but only suceeds in piercing his arm and having decided that Orochimaru was unworthy of having an Uchiha's body. Orochimaru proceeded to reveal his true body, a large white snake made of several smaller snakes, in order to initiate the body-switch process. Sasuke however cuts up Orochimaru's large snake body and seemingly kills him, only to realize that the vaporizing blood is turning into a poison and Orochimaru succesfully starts the body-switch process. Sasuke however stops the process like Itachi had done years earlier, but took it a step further by turning the switch against Orochimaru, absorbing him into his own body. Sasuke gained access to some of Orochimaru's abilities, but at the same time had to dedicate some of his chakra to suppressing Orochimaru.
During his battle with Itachi, Sasuke ran out of chakra, and Orochimaru was able to emerge through his signature hydra technique. He marvelled at the fact that he would finally have the chance to take Sasuke's body, but was immediately struck down and permanently sealed away by Itachi's Susanoo, as well as the Cursed Seal. In a separate encounter, Kabuto met with Naruto, and revealed that he had integrated some of Orochimaru's remains into his body, hoping to surpass his former master
Through a lil’ thicket, crouched a young she-wolf. Her pelt was of ebony black, stained with red. She also bore crystal hues that seemed to glow all the time. The hound was rather large for a female, and very well built. Much like a brute. She took on the name; Broken Kumac Insanity. Not that far in front of her, sat a bunny, nibble on some flowers. She wasn’t hungry, no, just bored. The pack didn’t need her right know, and her mate was just out. So, she needed something to do. There was a sudden sound that broke through the air, that caused the bunny to startle. A loud bark erupted Kumac’s vocal cords as she broke out of the bush, charging towards the bunny. She snapped at it’s heels as it took off. She wasn’t trying to kill it. She thought it senseless to kill an animal without reason. She just enjoyed the chase.