Though the game is titled after the comic book series Venom: Separation Anxiety, the story more closely follows the events of Venom's first limited series, Venom: Lethal Protector. The game's plot loosely follows Lethal Protector in the following ways:
Appearance of Spider-Man (in Lethal Protector #1)
Confronting the digger in San Francisco (as seen in Lethal Protector #1)
Discovering the underground city (as seen in Lethal Protector #1)
Appearance of The Jury (as seen in Lethal Protector #2)
Removal of five symbiote seeds to create five new symbiotes (as seen in Lethal Protector #4)
Spider-Man and Venom's escape from the Life Foundation (as seen in Lethal Protector #5)
Confronting the five symbiotes at the Life Foundation Headquarters (as seen in Lethal Protector #5)