Doctor Octopus threatens to harm Aunt May if Spidey ever puts on his mask again. Spider-Man must track down Ock before he has a chance to put his plan into effect.
Spider-Man must team with the former traitor, Scarlet Spider, to stop Doc Ock from reawakening a secret program designed to create evil duplicates of Spider-Man.
Spider-Man and Kid Arachnid arrive in the Noir Universe, where they have to prevent Mr. Negative from using the Siege Perilous to drain all the life and color out of the world.
Spider-Man and Miles, tracking the missing pieces of the Siege Perilous, travel to a tropical Pirate dimension, where they meet Web Beard, the Spider-Pirate.
With the Carnage Bomb already detonated, turning civilians into versions of Carnage, Spider-Man, Captain America and SHIELD Academy must band together to save New York.