Despite having seemingly returned to their normal lives, Kei Kurono, Masaru Katou, and Kei Kishimoto are forced back into the lethal game after Gantz's recent activity. The black sphere continues to summon recently deceased people to fight alien invaders. And having survived the two previous encounters, the trio are more than prepared for the upcoming missions. As they progress through the tournament's stages, the three proceed in their attempt to earn 100 points, which is said to be the only way to leave the parallel dimension for good. However, with the constant onslaught of alien invaders and the threat of imminent death, they must first focus on the task at hand—immediate survival.

Due to the ongoing serialization of the manga during the anime's production, Gantz 2nd Stage diverts from the manga's plotline midway and features an original ending.