In 1996, serial killer Cletus Kasady meets and falls in love with Frances Barrison at their childhood home of St. Estes; Barrison is taken away by the authorities to the Ravencroft Institute due to her mutating powers. During her transport, she attempts to escape using her sonic scream powers, attacking a police officer named Mulligan, who shoots Barrison in the eye and suffers hearing damage in his left ear due to the attack. Though he believes to have killed her, Barrison is later imprisoned in Ravencroft.
In the present day, Mulligan, now working as a detective and wearing a hearing aid, hires Eddie Brock to meet with Kasady as he refuses to talk to anyone except for Brock. During the visit, Cletus and Eddie appear to strike up a deal: Cletus will reveal the location of his victims' corpses and share secrets about his life, and Eddie gets to share the story and gain popularity, all while keeping Cletus off Death Row. Just as they are about to leave, however, Venom notices Cletus's wall drawings in his cell, revealing the locations of the bodies. With the corpses discovered and Kasady losing his end of the deal, he is sentenced to be executed via lethal injection. Kasady writes a letter to Brock inviting him to the execution. During their last interview before Kasady is sent to the injection chamber, Kasady insults Brock and unknowingly provokes Venom, who attacks him. Kasady bites Brock's hand to free himself, ingesting a part of the Venom symbiote through Brock's blood. Brock then meets with his ex-fiance Anne Weying, who tells him that she is now engaged to Dan Lewis.
During Kasady's execution, a red symbiote suddenly appears and blocks the injection. It then breaks Kasady free and introduces itself as Carnage, going on a rampage through the prison, killing many guards and freeing inmates before escaping. The two then make a deal: in exchange for helping Kasady break Barrison out of Ravencroft, Kasady will help Carnage kill Venom so it can be the only symbiote on Earth. Mulligan then calls Brock to tell of Kasady's escape and that a city-wide manhunt is now in progress. Unfortunately, Venom and Brock breakup when Venom, wanting more freedom to eat people, fights Brock in their apartment, detaching himself from Brock's body. Meanwhile, Kasady frees Barrison from Ravencroft before traveling to the ruins of St. Estes and burning it down.
Mulligan arrests Brock, suspicious of his interactions with Kasady, and interrogates him. However, Brock refuses to answer and contacts Weying as his lawyer. Brock declares that Venom has separated from him and that he needs him back to fight Carnage. Venom, hopping from body to body, returns to San Francisco. Weying finds him, convincing him to make amends with Brock. He bonds with her, and they break Brock out of the police station. Venom and Brock reconcile before bonding once again.
Kasady and Barrison then take Mulligan and Weying hostage. Barrison gives Lewis information on their whereabouts, who passes it onto Brock. Brock and Venom confront the villains at a church as they attempt to be married, and Venom fights Carnage. During the battle, Barrison seemingly kills Mulligan, while Venom struggles against Carnage. However, Venom notes that Kasady and Carnage lack true symbiosis; Carnage constantly attacks Barrison due to her powers, an act Cletus despises. Venom then provokes Barrison into using her sonic powers again, which causes both symbiotes to separate; Barrison is seemingly killed when the church bell collapses and crushes her. With the church tower collapsing, Venom bonds with Brock once again, saving him, then eats the disembodied Carnage symbiote before it can connect with Kasady again. Wounded, Kasady says that all he ever wanted from Eddie was his friendship. Eddie is sympathetic, but Venom is not, promptly biting Kasady's head off.
Brock, Venom, Weying, and Lewis flee the church as the police arrive. Mulligan's eyes flash blue, revealing his survival and possible powers. Brock and Venom later relax at a tropical island, wondering what to do next. In a mid-credits scene, as Venom tells Brock about the symbiotes' knowledge of other universes, they are suddenly teleported by a blinding light from their hotel room to another, similarly-shaped room. They are now in the Marvel Cinematic Universe, where they watch a news report of Peter Parker's exposure of his identity as Spider-Man.
