Legend has it that the human race is not the only dominant civilization living on Earth. Two other races exist in this world: the Makai (a demon race) and the Juujinkai (a half-man, half-beast race). Once every 3,000 years, a supreme being known as the “Choujin” (Overfiend) will emerge and bring balance to all three realms on Earth. In present-day Japan, after 300 years of endless searching, a Jujinkai named Amano Jyaku has discovered the presence of the Choujin inside high school slacker Tatsuo Nagumo. But now, Amano, along with his sister Megumi and their sidekick Kuroko, must protect Nagumo and his new girlfriend Akemi Ito from the Makai, who believe that Nagumo is not the Choujin, but an evil entity bent on destroying all living beings on Earth.
After giving birth to the Chōjin, Akemi reawakens in a hospital, along with Jyaku, who had barely survived a recent confrontation with the Chōjin (whose form constantly mutates between male and female). Destroyer God Tatsuo also reappears (after supposedly being killed by Kyō-Ō in Urotsukidoji: Return of the Overfiend) and continues his ravaging of Earth. Still in love with Tatsuo, Akemi runs out to find him.
Meanwhile, Jyaku is confronted by some of the Chōjin's new 'children', and engages them in battle. However, his efforts prove almost futile, as they are constantly regenerated by the Chojin. Akemi eventually finds Tatsuo, still in his God form, and pleads with him. He clutches her in his hand (similarly to the end of the first episode) and prepares to kill her. However, she is rescued at the last minute by Jyaku, although she condemns him for doing so.