n 1994, Heather Watkins, a bookstore employee at Shadyside Mall, is stabbed by her friend, Ryan Torres. He murders her and several other mall employees before he is killed by Sheriff Nick Goode. The media reports the massacre as the norm for Shadyside, which they dub the murder capital of the United States. Meanwhile, the neighboring town of Sunnyvale is its polar opposite, as it is considered one of the richest and safest towns in the country. Many of the Shadyside teenagers believe that this is the result of the witch, Sarah Fier, who placed a curse on the town before being executed for witchcraft in 1666.

Deena Johnson does not believe in the Fier witch and has recently broken up with her closeted girlfriend Sam, who had moved to Sunnyvale. Josh, her brother, spends his time researching the town's history, and her friends Simon and Kate sell drugs in hopes of eventually leaving the town. Deena and Sam meet again at a vigil in Sunnyvale for the victims of the mall killings, where a brawl between the students of Shadyside and Sunnyvale breaks out. While returning home, Sam's boyfriend, Peter, begins tailgating the bus carrying the Shadyside students, leading Deena to almost throw a large cooler at the car in retaliation. A sudden nosebleed causes her to lose her grip on the cooler and Peter's car to crash. Sam survives and sees a vision of Sarah Fier before being taken to the hospital.

The following night, Deena and her friends begin to be stalked by someone whom they initially believe to be Peter and his friends. However, when Deena and her friends visit Sam, Peter is killed by Skull Mask, who proceeds to murder several others in the hospital and is revealed to be Ryan. Sam and Deena seek help but fail to convince the police while Simon is attacked by Ruby Lane, one of Shadyside's past killers in 1965. The group realizes that the car accident involving Sam disturbed the grave of Sarah Fier and that Sam bled on her bones, resurrecting several Shadyside killers. Josh deduces that Fier's curse is the reason for Shadyside's history of killings which began following her execution. They attempt to offer her a proper reburial but are attacked by the Camp Nightwing Killer. Realizing that the killers only want Sam and are attracted to her blood, they set a trap at school in an attempt to destroy the killers by burning them, but the killers manage to reanimate.

Sam reluctantly agrees with the group to be sacrificed despite Deena's protests. They save her when it is discovered that C. Berman, a survivor of the Camp Nightwing massacre in 1978, died but was resuscitated. They attempt to call her but receive no answer. The group organizes a plan to kill and revive Sam using drugs from a supermarket pharmacy. There, Kate, Simon and Josh attempt to fend off the Shadyside killers but Kate and Simon are killed. Deena finally drowns Sam with her consent, causing the killers to disappear and revives her using a combination of EpiPens and CPR.

Afterward, the police decide to place the blame on Simon and Kate, as they were known for selling drugs. Sam and Deena reconcile and publicly come out as a couple. Later that night, while Sam is at her house, Deena receives a call from C. Berman who tells her that there is no escaping the witch. Sam, now possessed, attacks Deena but is subdued and tied up.