3×3 Eyes follows the adventures of Pai, the last remaining Sanjiyan Unkara (三只眼 吽迦羅 lit. triclops^?), and her new Wu (Chinesereading of 无; an immortal companion), Yakumo, as they desperately try to find a way to make Pai human so that she can forget her troubled past. Pai travelled to Tokyo searching for the artifact, but shortly after she arrived, a thief snatched her backpack and cane from her. A teenage lad, Yakumo, tackled the crook and managed to get the pack back for her, though the thief escaped with the cane. Yakumo took her to his work, where Pai was able to get cleaned up, and where she discovered that he was the son of Professor Fujii, an archaeologist she had met in Tibet four years prior. The Professor had been researching the legends of the Sanjiyans and had befriended her and offered to help her find the Ningen, only to fall ill and die. Pai had his last letter to his son in her backpack, which asked Yakumo to help Pai with her quest. Although he didn't believe his father's tales of Pai being a monster, he agreed to assist her.

Their discussion was interrupted by news reports of a giant monster flying over the city. Pai recognised the creature as her pet Takuhi, who must have been released from his home in Pai's cane by the thief, and who was now looking for her. Pai set out to retrieve him, with Yakumo close behind. However when Yakumo saw Takuhi fly towards Pai, the lad mistook the beast's welcome for an attack, and shoved Pai out the way; immediately Takuhi ripped into the lad, fatally wounding him. Unwilling to lose the boy she had been hunting for and just located, Pai's third eye opened, and she absorbed his soul. This restored his body, but tied him to her as her undead servant. Linked to her, he can only become human again when she becomes human. In the way of this goal are hordes of monsters and demons from the Shadow World, some desiring Pai's powers, others who seek the Ningen for their own. Yakumo can again become mortal and end his constant need to protect Pai because if Pai dies, then so will he. Along the way, they encounter many followers of the now-dead demon god Kaiyanwang, all of whom wish to kill Pai or siphon off her power in order to resurrect their deity and/or gain immortality.