3x3 Eyes: Sanjiyan Henjō is based on the manga and anime series 3x3 Eyes. Pai, a young girl from the immortal tribe of sanzhiyan, three-eyed demons of Chinese origin, wants to become a human again. She meets a Japanese teenager named Yakumo Fujii, whom she accidentally turns into a "wu", an immortal obedient servant of a three-eyed demon. Together, Pai and Yakumo try to regain their lost humanity.
This game can be considered a side-story to the series. The player does not control Yakumo, but an ordinary high-school student named Kenichi Yamamoto. Accidentally, Kenichi comes into contact with the world of demons, and now he needs the help of Pai and Yakumo to be freed.
The gameplay is standard Japanese-style adventure. The player interacts with the game world by selecting menu commands "Look", "Talk", and "Move". The game features animated cutscenes and (in its console incarnation) voice-overs.