Following the murders at Hillcrest Academy, a guilt-ridden and traumatized Laurie Strode (Jamie Lee Curtis) has been confined to a psychiatric facility, after killing a man whom she had mistaken for her murderous brother Michael Myers. As two nurses talk about what happened, flashbacks reveal that a paramedic had found an unconscious Michael in the school, before he suddenly awakened and attacked the paramedic, crushing his larynx so that he could not speak. Michael then swapped clothes with the unconscious paramedic, and left the school grounds undetected, as Laurie drove off in the ambulance she believed Michael was in.
On October 31, 2001, after three years of hiding, Michael re-emerges to attempt to murder Laurie again, who has been institutionalized at the Grace Andersen Sanitarium. Expecting his arrival, Laurie sets up a trap for him. After killing two security guards, Michael attacks and chases Laurie to the institution's rooftop, where her trap works and temporarily incapacitates Michael. However, Laurie's fears of killing the wrong person again get the better of her, and when she tries to remove his mask to confirm his identity, Michael stabs and throws her off the rooftop to her death.
A year later, college students Sara Moyer (Bianca Kajlich), Bill Woodlake (Thomas Ian Nicholas), Donna Chang (Daisy McCrackin), Jen Danzig (Katee Sackhoff), Jim Morgan (Luke Kirby), and Rudy Grimes (Sean Patrick Thomas) win a competition to appear on an Internet reality show called Dangertainment, directed by Freddie Harris (Busta Rhymes) and Nora Winston (Tyra Banks), in which they have to spend a night in Michael's abandoned childhood house in order to figure out what led him to kill. However, while setting up cameras throughout the house in preparation for the show, cameraman Charlie (Brad Sihvon) is killed by Michael, who has returned to Haddonfield. On Halloween night, equipped with head-cameras, Sara, Bill, Donna, Jen, Jim, and Rudy enter the house and separate into three groups to search for clues, while Sara's messaging friend Deckard watches the live broadcast during a party. During the search, Michael suddenly appears and kills Bill.
Donna and Jim discover a wall filled with fake corpses and realize that the show is a setup, before the former is killed by Michael. At the party, Deckard and other partygoers witness the murder, but only Deckard realizes that it was real. Meanwhile, Freddie enters the house dressed as Michael in order to scare the competitors, and is followed by the real Michael, whom he mistakes for Charlie. When Rudy, Sara, and Jim find Freddie in the Michael costume, he reveals the scheme to them and begs them to cooperate, telling them that they will all be paid well if the show works out. After Freddie leaves, the trio decides to gather up the rest of their friends and leave. Jen discovers Bill's corpse, and Michael decapitates her, in front of Rudy, Sara, and Jim, who soon realise that it isn't Freddie. Michael proceeds to kill Jim and Rudy before chasing Sara upstairs.
Locking herself in a bedroom, Sara begs for Deckard to help her. As the other party goers realize that all the murders were real, Deckard begins to message Sara on Michael's locations to help her avoid him. Sara runs into Freddie just as Michael finds them and stabs the latter. Sara runs into the tunnels and finds an exit leading to the garage, where she discovers Nora's body. Michael again arrives and attacks Sara, but a still-living Freddie finds them and fights Michael as an electrical fire starts in the garage. After electrocuting Michael, Freddie carries Sara to safety, leaving Michael to die in the burning garage. Later, Freddie and Sara are interviewed by the local news, during which Sara thanks Deckard for saving her life. Meanwhile, Michael is presumed dead and his body is taken to the morgue; however, as the coroner prepares to examine his body, Michael suddenly awakens.
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