The game revolves around an artifact known as the Tablet of Order and Chaos. When it is shattered into pieces during a fight between Spider-Man and Mysterio, it causes problems with multiple realities across the Marvel Universe. Madame Web calls on four versions of Spider-Man from four realities to assist in bringing the realities back into balance: the Amazing Spider-Man, Spider-Man Noir, Spider-Man 2099, and Ultimate Spider-Man. The player controls each of the four Spider-Men as they attempt to retrieve the tablet fragments from villains within their respective dimensions, who now possess new abilities granted by the tablet.