the film starts when a couple were having sex. Afterwards, the man showers while the woman goes to get herself a drink. After his shower, he discovers "You're Next" written in blood on the living room's sliding glass doors, beyond which lies the woman's dead body. He is then killed by the Lamb Mask. In the next scene, a wealthy family is seen going to their remote Missouri vacation house, which happens to be next door to the house in which the couple from the opening scene were brutally murdered. The mother, Aubrey, claims she hears something upstairs and wants to leave. Ignoring her warning, her husband, Paul, goes to investigate, but is startled by one of his sons, Crispian, who has just arrived with his Australian girlfriend, Erin.
The next day, Crispian's other siblings arrive. While cooking, Aubrey sends Erin to go to a nearby house to ask for milk, but there is no response as the two people inside were previously murdered. At dinner that night, family tensions are revealed as Drake, Crispian's older brother, who had previously made fun of Crispian for being weak and fat, then criticizes him for dating Erin, who is his former student and teaching assistant. Crispian's younger brother, Felix, and his girlfriend, Zee, show disinterest in the argument as the other family members attempt to calm the brothers. In the midst of the chaos, the gathering suddenly turns deadly when Tariq, Crispian's younger sister Aimee's boyfriend, is shot in the head with a bolt through a window. In the process of saving his mother, Drake is shot in the back with a bolt and later passes out from the pain, but survives. The family realizes that their phones have no signal, leading Felix to suggest that perhaps the attackers are using a jammer. Aimee attempts to escape the house to get help but is killed after running into a thin wire strung outside the front door at neck level, cutting her throat.
Erin begins to organize the family's defense, shutting all entries, gathering weapons, and sending a text message to the police, hoping that if her phone finds any small signal at some point, that the text will be sent. In the process of gathering weapons, she is attacked through a window by Tiger Mask, but stabs him in the arm, causing him to retreat. Aubrey lies down in her bedroom to grieve and rest, but is murdered by Fox Mask whom was hiding under her bed. Hearing her scream, the surviving family members run upstairs to find her dead body. On the wall, written in blood, are the words "You're Next". Lingering, Drake's wife Kelly discovers that Fox Mask is still under the bed. She escapes and runs to the neighbors' house, where she discovers the dead man's body. She is then butchered with an axe by Lamb Mask. Having discovered that their cars have been disabled, Crispian flees the property to seek help. Erin is attacked in the house shortly afterward but kills the Tiger Mask assailant with a meat tenderizer to the head. Upstairs, Paul discovers the killers had been hiding in the house before the family arrived, but he is murdered by Fox Mask in front of his youngest son Felix and his girlfriend, Zee. Their restrained reaction to Paul's murder leads to the revelation that Felix hired the masked assailants and planned the murders, hoping to inherit the family's fortune. They go downstairs and tell Erin that Paul is fine and resting upstairs.
Erin and Zee set up nails in wooden board traps near the window, hoping to catch the killers. Erin confides to Zee that she was raised by her paranoid father in a survivalist camp in the Australian outback, which she had not yet told Crispian about. Zee attempted to murder Erin from behind, but stopped when Erin almost saw her. Lamb Mask enters the house, in which he finds Tiger Mask who turns out to be his brother, dead on the floor, angering him. Erin and Drake who awakens are almost killed by Lamb Mask, but Erin saves him by stabbing Lamb Mask in the back, causing the assailant to flee the house. Felix and Drake go to the basement to collect potential weapons. Once alone, Felix kills Drake by impaling him with screwdrivers. Erin goes upstairs to try to find Paul, but finds him dead and is attacked by Fox Mask. She escapes by jumping out of the window, impaling her leg with a shard of glass in the process. She flees into the woods and is attacked by Lamb Mask, but makes it back to the house.
The Lamb Mask assailant sees a wooden nail board trap hastily placed in view under the window, and assumes its safe. He steps down and directly steps on a nail, through his boot and into his foot. Once inside, hiding behind a curtain and bandaging herself, Erin overhears a conversation between Felix, Zee, Lamb Mask and Fox Mask, thus discovering their involvement in the massacre. Her phone rings (Felix having turned off the jammer just before), giving away her hiding spot, but also alerting her that her text to the police was received. The Fox Mask assailant finds her hiding behind the curtains, but she throat punches him and makes her escape. Fox Mask, Zee, and Felix follow her, but Lamb Mask assumes she went into a different part of the house. When Lamb Mask attempts to enter through the window instead, Erin stabs him in the head with a screwdriver by hiding by one side of the window, killing him. Erin uses Tiger Mask's axe and a brick to make a booby trap for anyone entering the front door but Fox Mask comes in another way. Erin draws Fox Mask into the basement and distracts him with her camera, set to take photos automatically, and she kills him from behind with a wooden log and smashes his head.
Erin is then attacked by Felix and Zee in the kitchen. After incapacitating Zee, she forces a glass broken blender on top of Felix's head and turns it on, killing him, and then drives a knife through the top of Zee's skull, killing her. Felix's phone rings and Erin answers without revealing her identity. Crispian is on the other end, and thinking he is speaking to a quiet Felix, he apologizes for fleeing, revealing that he was part of the conspiracy as well. He returns to the house and tries to explain his actions when confronted by Erin. He promises to use the money to pay off her student loans and let her study full time, and tempts her with millions. He assures her that the killers were not supposed to harm her and leave her as a sole witness with no criminal record. Erin kills him by stabbing him in the neck and eye.
At that moment a policeman arrives, who, upon seeing Erin stab Crispian, shoots her in the shoulder. He calls for medics and backup, and attempts to enter the house. However, he goes through the booby-trapped front door despite Erin's attempt to warn him. As the axe hurtles towards his face, the film smash cuts to the end credits with the words "YOU'RE NEXT" written in blood.
