Michelle (Mary Elizabeth Winstead) packs her things and flees her apartment, angry over a dispute with her partner Ben (Bradley Cooper). While driving away, she is distracted after Ben calls her and her car crashes and goes off the road, flipped upside down. When she awakens, she discovers that she is chained to the wall in an unknown location. After reaching her phone only to receive no signal, a man named Howard (John Goodman) enters the room and tells her that he saved her life, and that the world outside is now uninhabitable due to the nuclear fallout from "an attack." Skeptical, but trying to be careful, she pretends to accept this reality. Once freed from her chains and able to walk with crutches, she meets Emmet (John Gallagher, Jr.) who believes Howard's story. During dinner, Howard snaps after Michelle flirts with Emmet in order to get the keys around Howard's belt. When she does and the situation calms, she throws a bottle in Howard's face and tries to escape. She makes it to the the threshold between the door of the air-locked bunker, only to be surprised by the sight of a car and a woman, whose skin is horribly disfigured and peeling, begging to be let in. Howard yells at her not to let her in. She ultimately doesn't, and returns to the bunker.
Now believing that the outside world is uninhabitable, Michelle tries to adapt to her new life in the bunker. Howard confesses to Michelle that he accidentally crashed into her car, and shows her a picture of his daughter, Megan, and tells her that her mother took her away from him and moved to Chicago. One night when the air filtration system malfunctions, Howard asks Michelle to crawl through an air duct to reset the air filter in a control room as he and Emmet cannot fit into the vent. She does so and discovers a small window on the roof of the control room, which has the word "Help" scratched from the inside as well as bloody earring on the floor. Suspecting that Howard might have killed Megan, Michelle tells Emmet about what she saw, and shows him a picture of Howard's supposed daughter that he showed Michelle earlier (with the same earring in the picture). Emmet tells her that the girl in the photo isn't his daughter but a girl named Brittany, who Emmet's sister went to high school with, and who went missing two years ago. Suspecting that Howard may have something to do with the disappearance of Brittany, they try to make their own hazmat suits and gas masks in order to escape, using shower curtains and plastic bottles. One night, Howard calls both of them in the living room, playing coy and asking what they're up to, showing them the scissors and duct tape they had been using. He presents to them a barrel containing the highly corrosive perchloric acid. When Howard starts getting angry, Emmet lies to Howard that he had been making a weapon because he wanted Michelle to respect him like how she respects Howard. Howard then immediately shoots Emmet in the head.
Some time later, Michelle's suit is complete and Howard comes into Michelle's room, discovering the suit hidden under her bed. Michelle runs out of the room and locks Howard in there. Michelle runs to the living room to try and find a weapon, when Howard appears behind her. She knocks over the barrel of acid onto the floor and Howard slips on it, burning him. The acid causes the wire in one of the lamps to short out and cause an electrical fire. Michelle runs back to get the suit and manages to get to the air filtration room via the vent. Finally outside, she sees birds flying, takes off her mask off, and discovers that the air isn't toxic. She then sees a giant alien spaceship hovering over the corn crops. The bunker explodes due to the fire, which attracts the ship. She runs to a car outside the bunker, and the car alarm goes off, attracting an alien. She runs into the barn to escape from the alien and manages to get out and runs to Howard's truck. The ship reappears and drags the truck in the air, while Michelle finds a lighter, magazine and a bottle of alcohol. Lighting it on fire, she throws it into the mouth of the ship/alien. The ship/alien explodes, the truck is dropped to the ground and the screen cuts to black.
When Michelle comes to, she gets out of the truck and gets into the car. After a failed start, the car's engine roars to life and Michelle drives away, knocking over a mailbox that says "10 Cloverfield". She hears a distress call on the radio saying that areas north of Baton Rouge have successfully fended off the alien invasion while others to the south need more assistance, specifically that there are survivors in Houston in need of medical assistance and help from those with combat experience. She stops the car, decides what to do, and turns the car to go to Houston. Thunder and lightning reveals more spaceships in the sky.