A new gang called the H-Bombers have blown up the Carlyle building, and Spider-Man comes in to save the day. He beats the bombers and saves a woman from being killed. The next day, Peter Parker narrates: "Just another day in the life of your friendly neighborhood Spider-Man! Lately, things have been going my way. I got the girl and New York finally likes me. Not that there are problems, but there is this new guy Eddie Brock at the Daily Bugle, and he is really starting to get on my nerves. Harry, my best friend, won't talk to me. On top of that, new gangs have been dividing up the city, still its nothing I can handle. One weird thing, there hasn't been any big super villian around since Doc Ock. I had this bad feeling that the sky is gonna fall or something and soon."
Spider-Man finds out that the H-Bombers aren't the only gang terrorising the city. He finds out that there are other three gangs in the city: The Apocalypse, the Arsenic Candy, and the Dragon Tails. However, he makes short work of the Apocalypse, who attacked the subway and the power plant, and the Arsenic Candy, who attacked a theater, a factory and an abandoned warehouse with hostages. The H-Bombers later attack the subway station too, but Spidey was able to stop them.
Spider-Man takes Mary Jane Watson, his girlfriend, on a thrill ride, and stops by central park. Mary Jane asks how things been with Harry Osborn, and Peter responds that he has tried everything and Harry thinks he killed his Dad, Norman Osborn. Mary Jane tries to comfort him and tell him it wasn't his fault. Nearby, a symbiote inside a meteor crashes nearby and attaches to Peter's shoe. Meanwhile, Harry sneaks into the secret Goblin lair, and goes into a chamber filled with green smoke, and puts on his Goblin armor.
Peter's college science teacher Dr. Connors, records a tape explaining that he has studied lizard DNA and that lizards can grow new limbs after they are accidentally cut off. So he decides to inject lizard DNA into him to grow a right arm (which he lost when he was in the U.S. army). The experiment turns out okay and Connors regrows his arm, but the experiment is far more than imagined and transforms into a giant lizard and knocks over the camera that he was using to record his investigation. Peter walks pass Dr. Connors' lab and hears strange noises coming from there. He finds out what happened and follows Connors into the sewers, where the Lizard already turned other people into lizards, too. Spider-Man then follows and defeats the Lizard but the Lizard escapes deeper into the sewers, and Spidey can't go any further. Peter changes into his clothes and worries until Harry (now the New Goblin) appears out of nowhere and attacks Peter. They go on a high-fly battle on New Goblin's glider, but Goblin is defeated and knocked unconscious by Peter's webbing, which he attached to a building. Peter brings Harry to a local hospital, where he will be treated. Meanwhile, an escaped convict Flint Marko tries to escape from the police and falls into a cockpit full of sand where scientist are mutating sand and Flint turns into sand.
Spider-Man foils the H-Bombers plans once again, who were planting bombs all over Financial District. The H-Bombers decide to attack the Daily Bugle kidnaps J. Jonah Jameson. It was revealed that Luke Carlyle, one of the richest people in New York, was The Mad Bomber, the leader of the H-Bombers all along. Spidey foils the H-Bombers' plans and saves Jameson from The Mad Bomber.
Spider-Man finds out about a science corporation called MechaBioCon, where a scientist named Dr Stillwell captured and tested Mac Gargan/Scorpion (who escaped his first encounter with Spider-Man in the subway station two years ago.
Spider-Man goes to the city to chase and battle Scorpion in the city and then goes to sleep due to a very tiring day.
During his sleep, the symbiote consumes Peter, leading Peter to have a new jet-black suit. The new symbiote suit makes him stronger, more agile, and more aggressive. Marko, now the Sandman, recently robbed a bank, and is headed for the subways. Spider-Man pursues him, and eventually defeats him, washing him away in a sewer line.
Brock and Peter both are given an assignment by their boss, J. Jonah Jameson: catch Spider-Man robbing something, and the one who does gets a promotion. Brock attempts to cheat by paying someone to pose as Spider-Man. The real Spider-Man appears, now influenced by the black suit, breaks Brock's camera and punches him. Brock tells him that he has many more cameras, and automatically photographs Spider-Man punching him. Spider-Man is able to recover the cameras and Brock swears revenge.
Peter gives Mary Jane a ride back to her apartment after a horrible date, where under the influence of the black suit, he alienates her. After acting too bossy and asking her to shut up, she decides to call off the relationship, which saddens Peter. Peter decides to go to a church, where he attempts to remove the symbiote suit, and successfully releases its bond to him. Unfortunately, Brock secretly finds and watches Peter unmask himself, and attaches to the symbiote, becoming Venom.
Venom finds a still-alive Sandman, and blackmails him to work together to defeat Spider-Man, or he will kill Sandman's daughter, Penny. Sandman eventually agrees. They kidnap MJ, so Peter suits up again in the red suit as Spider-Man. He goes to the construction site where Venom and Sandman are holding MJ captive in a taxi. He fights Venom and Sandman while Harry, recovered from his head injury, decides to help Peter rescue MJ as the New Goblin. Harry arrives and rescues MJ, and fights a giant Sandman which he defeats. Harry attempts to help Spider-Man fight Venom, but is killed in the process. Peter eventually defeats Venom by weakening him with sonic vibrations then dropping the two of them off a building. He survives as Venom is impaled by a steel bar.
Peter mends his relationship with MJ, and Sandman, still alive, is reunited with Penny, who has just been rescued by police.
