The game begins with Spider-Man on a quest for Mary Jane Watson. At the same time, New York City is plagued with symbiotes. After encountering Mary Jane with Luke Cage, Spider-Man is attacked by a mysterious figure. He recounts his account of how his fight with Venom ended with a piece of the symbiote attaching himself during a flashback to four days earlier. After her encounter with Venom, an injured Mary Jane is sent to the hospital, where she meets Luke Cage in the middle of a gang war. Spider-Man and Luke Cage hunt down the city’s gang leaders, the Roaring Sevens and the Park Avenue Gangs. He manages to get them to join a meeting in a Harlem park.
Outside the meeting site, Spider-Man discovers high-tech assassins on the buildings after defeating them and leaving Cage to deal with of the gangs. He traces the killers to the boss. He ends up confronting the black cat, who appears to be working with the boss. After a brief battle, Black Cat reveals that he is working for the boss. The duo join forces with Moon Knight to stop the Kingpin’s illicit activities. After a fight with Vulture, Spider-Man encounters many of the kingpin’s henchmen atop the Daily Bugle. They are attacked by symbiote-infected civilians. A News Helicopter Spots Spider-Man throwing one of the civilians out of the building, his distress unknown to the police.
The police now believe Spider-Man is a murderer. Wolverine, believing that Spider-Man is infected by the symbiote himself, approaches him in Hell’s Kitchen. After a battle, the two end up resolving their differences and begin hunting infected civilians together. Spider-Man discovers Venom throwing people into symbiote pods, turning them into monsters. After a city-wide battle, Venom escapes, but many of the pods are destroyed. A SHIELD. Team, led by Black Widow, arrives and quarantines New York City, setting up camps for the symbiote-controlled citizens. Electro attacks one of the camps looking for his sister, Spider-Man defeats him but he is shot by Black Widow, while Spider-Man berates Black Widow for her actions, Sister Electro gives her symbiote to him to cure – infecting him in the process.
Spider-Man devises a plan to get Tinkerrer off Ryker’s Island to use his scientific genius to find a countermeasure to the symbiotes. After making several support efforts from Black Widow, Moon Knight, King Pin and defeating symbiote-controlled Electro, Spider-Man helps Wolverine clear a church of civilians outside the area and Wolverine himself is affected. Spider-Man is able to free him from it. Spider-Man searches for Mary Jane. After finding her, he helps her and Luke Cage clean up Harlem. He visits a building where he finds a symbiote-controlled black cat, apparently the leader of the hive. He defeats her, and the Tinkerrer completes his device.
