The game's storyline kicks off with a tutorial level where Spider-Man prevents the H-Bombers from blowing up the Carlyle building. The next day, he investigates strange lizard-like beings in Central Park and continues battling the H-Bombers, thwarting their attempts to destroy the Daily Bugle's Printing Plant and Regional Office. That night, while having a conversation with Mary Jane in Central Park, an alien symbiote from a meteor attaches itself to Peter's shoe. After taking Mary Jane home, Peter is attacked by Harry, who has become the "New Goblin" to avenge his father's death. Peter defeats Harry, takes him to the hospital, and then returns home, where the symbiote envelops him, creating a black Spider-Man suit that enhances his abilities and increases his aggression. Meanwhile, an escaped convict named Flint Marko becomes the Sandman after a mishap with an experimental particle accelerator fuses him with sand. The next day, the H-Bombers attack the Daily Bugle and kidnap J. Jonah Jameson, but Spider-Man rescues him. He then confronts and defeats the Bombers' leader, Luke Carlyle, a businessman turned criminal due to a story published by Jameson that ruined his company. Later, Peter investigates the disappearance of his science teacher, Dr. Curt Connors, and discovers that he has transformed into the Lizard through experiments with a lizard DNA serum. Pursuing the Lizard through the sewers, Spider-Man finds that he has transformed others into similar creatures with plans to invade New York. Spider-Man foils the plan but the Lizard escapes deeper into the sewers. When Spider-Man encounters him again, the Lizard is in a fight with Kraven the Hunter. Spider-Man intervenes and defeats Kraven before overpowering the Lizard and returning Connors to his human form. As Spider-Man cures the other victims of the lizard transformation, Connors helps him investigate the symbiote's dangerous potential after fully recovering. An assignment from Jameson leads Spider-Man to face a vampire, whom he defeats and takes to Connors. Connors identifies the vampire as Dr. Michael Morbius, a renowned biochemist. Morbius claims his transformation was caused by his wife Shriek, whom Spider-Man tracks down and defeats. However, she escapes, and Spider-Man later battles Shriek's gang, the Waste Tribe. He eventually locates Shriek and brings Morbius to her in hopes of a cure, but she turns Morbius against Spider-Man instead. After defeating Morbius, Spider-Man confronts Shriek, using the symbiote to counter her powers. Defeated, Shriek uses her abilities to cure Morbius before falling into a coma. Spider-Man leaves her in Morbius' and Connors' care and departs. Later, Peter learns that Eddie Brock has been impersonating a black-suited Spider-Man to frame him as a criminal and secure a promotion. After humiliating Brock as Spider-Man, Peter exposes the scheme and earns the promotion, leading to Brock vowing revenge against both Spider-Man and Peter. As the public becomes increasingly alarmed by Spider-Man's violent tendencies while wearing the symbiote suit, Spider-Man plans to retire it. However, he spots Marko robbing an armoured van and chases him into the subway. Unable to defeat Marko, Spider-Man dons the symbiote suit and is ultimately consumed by its aggression. Discovering water as Marko's weakness, Spider-Man opens a pipe, releasing water that disintegrates Marko into mud. Later that night, the symbiote's influence on Peter frightens Mary Jane during their date and a confrontation with robbers. Peter realizes the symbiote's negative impact on his behaviour and heads to a nearby church to remove it. He succeeds thanks to the church bell's sonic vibrations, which weaken the symbiote. However, the creature bonds with Brock, who followed Spider-Man to the church. As Venom, Brock, aware of Peter's identity as Spider-Man, blackmails Marko into helping him kill Spider-Man by threatening Marko's daughter. They kidnap Mary Jane to lure Spider-Man, but Harry, now recovered, comes to their aid. Harry rescues Mary Jane and Marko's daughter and helps Spider-Man defeat Marko before Venom tries to kill him. Spider-Man defeats Venom by using sonic vibrations to weaken him, but Brock presumably dies as the symbiote leaves his body. Following these events, Spider-Man reconciles with Mary Jane, and Marko is reunited with his daughter. He apologizes to Spider-Man and leaves peacefully. The game concludes with Spider-Man resuming his ongoing battle against crime, emphasizing that the best way to honour and remember his loved ones is by never giving up on being Spider-Man.