The game is set during a large-scale assault across the galaxy led by Annihilus and the Annihilation Wave, a force that threatens countless worlds. As the conflict spreads, heroes from Earth and beyond—including Nova, Spider-Man, Wolverine, Phyla-Vell, and Captain America—are drawn into a wider effort to stop the invasion. The story follows their attempts to contain the destruction and confront Annihilus before the balance of the universe is lost.