The first part of the script deals with Peter and MJ's on-going relationship. The first scene has Peter attend one of MJ's stage events. As the audience applauds in approval, we pan up to see Harry Osborn's reveal, leering at Peter.
Next, as Peter and MJ part (MJ getting into a cab driven by Chris Tucker) in a comical moment, Peter removes a ring from his pocket...an engagement ring. As Peter is walking to his apartment, he's attacked by The Goblin (Harry Osborn). After an intense aerial fight sequence that deals with Peter not only trying to save himself from injury but also save his engagement ring. Finally, the fight goes into an alley where Peter creates a web that Harry flies straight into and is knocked unconcious. Peter removes his facial mask to see that it is indeed Harry. Harry, not remembering anything (effects from the human performance enhancers) promises to go get help.
Next we're introduced to Eddie Brock, a rival photographer at the Daily Bugle that always competes with Peter. There is tension between the two from the get-go, mostly on Brock's behalf. JJ informs both men that there is a promotion available, and that the man who gets more incriminating shots of Web-Head will get the job. JJ assigns them both to take pictures at the Spider-Man Appreciation Day event the next day.
We see the arrival of the symbiote to earth, debris smashing into buildings in Times Square, and finally the meteorite crashes in central park. Meanwhile. We see Harry, now a full-blown alcoholic, in his father's den. He continues to hear the voice of his father inside his head. He tries to fight it off, but its just too strong. Harry goes into the Goblin lair, only to see his father's reflection in broken glass. Norman tells Harry to avenge him. A pumpkin bomb explodes right next to his face, awaking him, as it was all just a nightmare, and Harry is slumped over a table, an empty bottle of whiskey in hand.
We're re-introduced to Mr. Ditkovich and Ursula as Peter goes to his apartment. Peter and MJ go on a date that night as we soon learn that MJ is having problems with her father, her acting career (not being able to land a movie role) and is perhaps a bit jealous of the fame that her significant other is gaining as Spider-Man. Peter talks about how he revealed himself to her and everything that has happened, before proposing to her. MJ says yes.
Next, Peter is making his way home as the symbiote from the meteor clings to the bottom of his shoe. He goes back to his apartment, and goes to sleep, as the symbiote manifests itself under his bed and lies in wait.
At the Spider-Man Appreciation Day event, Peter meets up with MJ, and we learn that Brock and Gwen are ex's. They talk a bit as Peter makes sure that MJ assures him she's not upset about the event. Next, Peter quick-changes into Spidey, making his appearance. Gwen, for being saved by Spider-Man, presents him with the key to the city. She also steals one of his patented upside-down kisses. Brock is immediately infuriated. MJ is too discouraged.
The event is interrupted by Sandman, who has hijacked an armored car. Sandman goes at it with Spidey. Spider-Man, attempting to save everyone, is beaten for the time being as Sandman makes a get away. Brock is there to snap pictures of the down-and-out Spidey. We see more tension between Brock and Gwen, as Gwen tells Brock that she never wants to see him again. He immediately blames Spider-Man. After returning Gwen to her father, Captain Stacy tells Spider-Man that Sandmans name was Flint Marko, who the police force was chasing priory escaped custody.
Peter, exhausted, slumps up the stairs in full Spider-Man outfit infront of Ditkovich, who just stares wide-eyed. Peter goes to sleep, as the symbiote attaches itself to him. The screen becomes entirely black. Next, Peter wakes up, hanging upside down above the city. He sees his reflection in the side of a building in the Spider-Man costume, however it has become entirely black (the symbiote suit) Peter learns to control his new suit. Peter swings through the streets and comes across Mysterio who he throws one punch to the dome, smashing it. Bruce Campbell does some funny one liners.
The next morning at the Bugle, JJ is going crazy over the Sandman pictures and Spidey being beaten. In a comedy moment, Hoffman and JJ name the Sandman. JJ praises Brock for his photo's.
Peter wakes up as he realizes he's late for work. He sees that the Symbiote suit will not come off. Hurrying, he rushes out the door. Ditkovich confronts him about Spider-Man, as Peter tells him that Spider-Man comes over every Tuesday night to play poker. Slowly, we start to see the symbiote taking its toll on Peter. He explodes Aunt May. Meanwhile, we see MJ's father hitting her up for money. Peter gets into a confrontation with him and ends up laying him out. MJ and Peter get into a fight over it. Peter also learns that the symbiote can transform into an article of clothing, in particular a leather jacket and the mask portion of the symbiote actually becomes Peter's hair, turning jet black. His eyes even change. He starts to gain a pale complexion. Peter goes out on a date with Gwen Stacy, and has seemingly become more aggressive even in the courting of women.
Meanwhile, Harry wants to meet MJ. They meet in central park as Harry stalks MJ first. They finally come face-to-face and talk about Peter. Harry who tries to force himself on MJ as she runs out.
Peter swings to Dr. Conners lab. Conners takes a sample of the Symbiote and starts to study it. We also see clues of him working on the lizard DNA project to replace his arm.
There is another Sandman bank robbery. Spider-Man and Sandman battle, as Sandman makes a crack about he was the first one to get to the bank therefore the money is his! The fight goes down into the subway. The symbiote tells Peter that it was Sandman who murdered Uncle Ben through several flashing daydreams. Sandman is doused with a giant wave of water as Spidey gets away. Sandman reforms at his grungey home.
Meanwhile, there is tension between Gwen Stacey and her father, who is heading a task force to take down Spider-Man. In one scene, Symbiote Spidey actually fights the police. Spidey is shot several times but learns that bullets do not affect the symbiote suit.
Meanwhile, MJ gives Peter his ring back and tells him she cannot marry him. With that, MJ gets on a train and leaves New York. We see Peter drop the ring into an incinerator. Next, we see that Dr. Conners has tested the symbiote sample and has concluded that its weaknesses are loud sound and heat. Peter, being tortured by the symbiote swings to a cathedral. Meanwhile, Brock follows him. As Peter swings into the belltower, he starts to ring the bell as the symbiote is weakened. He rips it off just as Eddie enters and sees that its Peter. Meanwhile, the symbiote lands on Brock and begins to bond with him. Peter swings off and inside the cathedral, Brock is taken over by the symbiote and he becomes a steaming husk, just as the task force to take down Spider-Man arrives. They enter the cathedral as the husk explodes and VENOM emerges. Venom single-handedly takes out the task force.
Harry still struggles with the voice of his father inside his head. Meanwhile, back at his apartment, and looking at a photo of himself and MJ, Peter realizes that he truly loves her. He meets up with Captain Stacy who informs him Gwen has been kidnapped by Sandman. Sandman takes Gwen to the top of a construction site. Peter, changes into his old Spider-Man costume, faces Sandman at the construction site. As Peter and Sandman battle, Gwen is dropped, and Peter has no choice but to try and save her, and does.
Meanwhile Brock, under complete control of the symbiote needs to kill Spider-Man as the two battle as it goes to a construction site. Venom hits the scene. Soon, Sandman begins to absorb sand around him as he starts to grow huge. He creates giant sand pits as Spidey jumps over them, with Venom leaping after him, and Sandman slamming down his giant malice and sledgehammer. Soon, Venom has beaten Spider-Man. Sandman attempts to finish him off but Venom takes a bite out of Sandman, making him not able to hold himself together (but not dying!), saying that HE is the one who will take out Spider-Man. Just as Venom is about to kill Spider-Man, Harry/Goblin hits the scene in full goblin gear (but with and alternate paint scheme). Harry and Spider-Man fight against Venom. Just as Venom is about to deliver the death blow once again to Spider-Man with one of his tentacles, Harry dives in the way and takes the hit. Peter and Brock race through the city ending back up at the church.Peter begins to ring the bell like crazy making the symbiote leave Brock. Venom defeated, Sandman and the symbiote missing, Harry dies in Peter's arms and tells him that he was sorry.
The closing scenes show Peter and Captain Stacy at Harry's funeral. He walks off as roses are dropped on Harry's casket. Pan up to see Norman Osborn, smiling. The last scene we find Peter and Aunt May walking away from the cemetery, she reveals that she's always known that he was Spider-Man. The camera pans down to a water run off in the street and the camera goes through the pipes ending up in the police cell room of Brock and Cassidy. The credits roll.