Scream is a horror film. The story is set in motion with the brutal murders of high school students Casey Becker and her boyfriend Steve, classmates of Sidney Prescott. The killer uses famous movie clichés as his means of killing.
The timing of the tragedy is hard on Sidney, who is attempting to cope with the anniversary of her mother's rape and murder. The following night she is contacted by the same person who killed Casey and Steve, a mysterious man dressed in a ghostly costume named Ghostface. Ghostface taunts Sidney over the phone and then attacks her in her home.
Reacting to circumstantial evidence, Sidney accuses her boyfriend Billy Loomis of being the attacker. Because her father is away on business, she spends the following night with her best friend Tatum and her brother Dwight "Dewey" Riley, a deputy on the police force. While there, she receives another taunting phone call from Ghostface, who tells Sidney that she "fingered the wrong man...again."...which implies that the man convicted of killing Sidney's mother, Cotton Weary, was actually innocent. This phone call seems to clear Billy, who is still in jail. Suspicion falls on Sidney's father, who turns out to be missing.
Sidney is forced to deal with the scandalization of her attack by tabloid television newswoman Gale Weathers. Gale is responsible for a book accusing Sidney's mother of having an affair with Cotton Weary and essentially calling Sidney an outright liar, leading to bitter mistrust between Gale and Sidney.
When word gets out that the killer is still loose, school is canceled as a precautionary measure, leaving the building abandoned. Despite the closing, the principal is killed while in school. Unaware of the principal's fate, Tatum's boyfriend Stuart "Stu" Macher throws a party; among the guests are Billy and Sidney, who reconcile through sexual intercourse, and film buff Randy Meeks, who explains to the other party-goers the genre conventions a movie character is required to follow in order to survive a horror film. Meanwhile, Tatum goes into the garage to get some more beer for the party, but instead gets killed by Ghostface.
Gale, sensing the potential for a scoop, crashes the party and hides a video camera inside the house. As Dewey and Gale investigate the mysterious appearance of Mr. Prescott's car, the party-goers receive word of the principal's death and most of them head to the school. Ghostface starts to stalk those who remain behind, murdering Gale's cameraman Kenny and wounding Billy, Dewey, and Sidney; Gale is injured in a car accident.
Sidney encounters Randy and Stu, who both accuse each other of being the killer; not knowing which one to trust, Sidney locks them both out of the house.
Billy falls down the stairs, seriously injured, and lets Randy into the house. Randy claims that Stu has gone mad, but Billy replies that "We all go a little mad sometimes" (quoting a line of Norman Bates from Psycho) and shoots Randy. Billy and Stu reveal that they are both the killer, and have been using a voice-changing device to make them seem like just one person over the phone.
They also reveal that they had murdered Sidney's mother the previous year and then framed Cotton Weary for the crimes; similarly, they plan to frame Sidney's father for their current murder spree by planting evidence on his body. They stab each other to create the illusion that they have been attacked by Sidney's father, but Billy cuts too deeply, and Stu starts to die.
Gale attempts to rescue Sidney and her father, but she is easily subdued when she fails to disengage the safety on her gun. However, Gale's interference does serve as a distraction which allows Sidney to escape. She returns to taunt and attack Billy and Stu; in the struggle that follows, she is subdued by Stu and Billy, she kills Stu by pushing a television onto his head ,and seriously injures Billy.
Randy regains consciousness after surviving his gunshot wound, but is then punched in the face by Billy, stunning him. Just when Billy is about to kill Sidney, Gale saves Sidney's life by shooting him. Sidney, Randy, and Gale take one last look at Billy's body. Presumably dead, Billy springs to life one more time (a horror convention which Randy had predicted), but Sidney kills him quickly with a bullet to the head ending the murder spree of Billy Loomis and Stu Macher.
In the epilogue, Dewey is carried away on a stretcher, wounded but alive, and Gale makes an impromptu news report on the events of the previous night as the authorities arrive.