In the year 2201, one year after the Yamato saved Earth from radioactive contamination, a new threat emerges. The Yamato makes its final journey to save the Earth from this new threat. Earth has almost recovered from the battle against Gamilus, and reconstruction has expanded to the other planets. When former Yamato crew-mates discover a strange, garbled message that seems to be coming from a white comet headed towards Earth, they hijack their old space fortress and begin a new battle.

When aliens known as the Oni threaten to invade the Earth, they promise to leave under one condition—a randomly-chosen human must win a one-on-one game of tag against Lum, the beautiful daughter of the Oni leader. The "lucky" person selected happens to be the lustful and unlucky high schooler Ataru Moroboshi. Given 10 days to attempt to grab Lum's horns, Ataru realizes how impossible the challenge is as he is faced with Lum's extraterrestrial powers. Motivated by a promise of marriage from his childhood friend Shinobu Miyake, Ataru manages to catch Lum off guard. He mistakenly grabs hold of her bikini top first, but he eventually achieves his true goal. Although the game is over, Lum misunderstands that she is the one whom Ataru wants to marry, and she decides to move in with him. The poor student constantly tries to shake off the clingy Lum while doing his best to reconcile with his desired fiancée. After Ataru's heroic feat results in such a disastrous outcome, it is questionable whether luck will ever be on his side.

At the millennial edge, the concluding battle for humanity's future is staged. Kamui Shirou's destiny has been decided as he returns to Tokyo to face his ultimate challenge. The Dragon of Heaven, defenders of the Earth, stand ready to protect the world from the Dragon of Earth, the seven angels of legend, who embrace the devastation of the planet to bring about its purification. Now Kamui must decide which side to fight for although he finds the idea utterly unappealing. It isn't until realizing that his two childhood friends, Fuma and Kotori Monou, are in grievous peril that Kamui decides to step into his fated position in the climactic struggle of the Year of Destiny: 1999.

High school girl duo Popuko and Pipimi are back and more unhinged than ever after their initial efforts to create a full-fledged anime production were met with a great reception. With no regard for their audience, they continue to live their reckless everyday lives consisting of comedy skits and parodies of epic proportions. No one is immune to the effects of their antics—including hapless live actor Shouta Aoi, who is on the run and stuck trying to be a hero in the wrong series.