A space shuttle piloted by J.J.'s son, John Jameson, crash lands on the Tri-Borough Bridge carrying two strange meteors—one that could provide a new nuclear fuel and one that contains an alien substance. The first is stolen by the Kingpin's henchman, the Rhino, just as Spider-Man arrives to save Jameson and the co-pilots. When the Rhino sends the aircraft off the bridge, Spider-Man emerges from the water with a dark stain covering his costume. Exhausted, he heads for home, only to awaken hanging from a skyscraper, now clothed in a black version of his costume.

Spider-Man goes after Eddie Brock for libeling him, as he is now being stalked by bounty hunters at every turn. After being reassured by Mary Jane that he has changed, he seeks help from Dr. Curt Connors who discovers that the suit is alive, and Peter is the host organism.

The Kingpin is furious at Spider-Man and sends the Shocker and the Rhino out to finish him off with the aid of another new invention of Alistair Smythe. Meanwhile, Eddie Brock, as the symbiote creature Venom, is busy playing cat and mouse with Spider-Man, intruding on Peter's private life and making it clear he knows the web-slinger's secret identity. To make matters worse, Peter soon realizes that the pumped-up Eddie as Venom is stronger than he is.

Under the psychiatric care of Dr. Kafka, Eddie Brock has come to believe that Venom is a figment of his imagination. Then Baron Mordo tempts Eddie to a reunification with the alien symbote that makes him as powerful as Venom.

Spider-Man and Venom must put aside their differences and help Iron Man stop Carnage and Baron Mordo from releasing Dormammu.