The game starts with a recap of what happened in the Venom storyline and Peter Parker's first fight with Venom before he disappeared, which had Peter and Venom fight from the high school football field on a rainy night and then the battle spans over to the middle of a street where Venom is believed to be killed by a downed, live powerline in Peter's point of view.
Three months later, Peter Parker has reassumed his normal life and has forgotten about Eddie. After a fight with the Shocker, Spider-Man is challenged to a race by the Human Torch whom Spider-Man beats.
Meanwhile, Eddie, who is actually alive, has been feeding on people randomly in a nearby park and proves his strength in a fight with Wolverine, who was the owner of a motorbike Venom threw through a bar.
After a fight with a Version 2 of the R.H.I.N.O., Spider-Man gets his first foreshadowing of Eddie returning when his Spider-Sense overloads. That night, Silver Sable and her Wild Pack attack Venom who easily escapes. During a field trip to the Metropolitan Museum of Art, Peter gets his "Eddie headaches" again and fights his former friend on the roof. However, Venom is later captured by Silver Sable.
Kept imprisoned in an energy cage, Bolivar Trask and Adrian Toomes convince Eddie to test the Suit for them as they knew Eddie and Peter's parents. His first test is going up against the recently escaped Electro where they fight over a knocked out Spider-Man in Times Square. Venom won't let Electro kill Spider-Man and ends up fighting and defeating him. Before Venom can eliminate an unconscious Spider-Man, S.H.I.E.L.D. interferes and this causes Venom to escape. Nick Fury wakes up Spider-Man who scolds SHIELD for not keeping the villains they have in custody permanently imprisoned...