In the opening scene, a woman named Michelle (Mary Elizabeth Winstead) is looking outside her window. She's on the phone with someone, arguing. Michelle then packs a bunch of her belongings and leaves her home.
Michelle drives far from the city down to the rural area. Her fiance Ben (voice of Bradley Cooper) calls her. She answers but only lets him talk and say how sorry he is, and that she shouldn't leave him just like that. Michelle hangs up. Ben calls again, and Michelle takes her eyes off the road for a second when her car gets slammed by a truck, causing her to roll into a ditch.
Michelle wakes up with a head wound in a small room with a needle in her arm that's hooked to a saline drip. To her horror, she sees her leg is chained to a pipe. She grabs her saline drip pole and pulls her phone toward her to call for help. Unfortunately, there is no signal. Someone comes downstairs to open the door to the room. It is a man named Howard (John Goodman). He claims to have rescued Michelle from the car accident and is keeping her alive. Howard offers Michelle a pair of wooden crutches to help her remain mobile with her leg injury sustained from the car crash, and tells her to "get good on those" before leaving the room.
Michelle sets about carving the tip of one of the crutches to sharpen it into a weapon to attack Howard with. The next time Howard shows up, Michelle tries to stab him with the sharpened crutch unsuccessfully, but Howard quickly grabs her and sedates her.
When she comes to, Howard calmly explains to Michelle that there has been an attack on the surface, and that the air up there is unbreathable, so he brought Michelle down to the bunker beneath his farm. Howard brings Michelle up to the airlock to see what's going on outside. Nothing appears unusual, but Michelle spots Howard's truck with red paint on the side, and she recognizes it as the truck that hit her.
From the bedroom, a clattering sound is heard from outside. Howard goes to yell at someone off-screen. Michelle leaves the room and finds a younger man named Emmett (John Gallagher, Jr.). His arm is broken, and Howard tells Michelle that Emmett knocked over a shelf with a week's worth of food.
Emmett appears more friendly than Howard. He explains that he willingly joined Howard in building the bunker, Emmett claims to have seen the attack occur, describing a red flash and running to get inside, which he says explains his broken arm.
Howard makes Michelle and Emmett join him for dinner like a family. Michelle engages in pleasant conversation with Emmett that appears sort of flirty, causing Howard to angrily respond. He warns the two of them not to behave like that. When he's not looking, Michelle grabs his keys. A rumble occurs overhead, distracting everyone but giving Michelle a chance to smash a beer bottle over Howard's head. She runs out toward the airlock and tries to get out. Michelle stands in the airlock between the outside and the inside as Howard begs her not to go outside. A woman (Suzanne Cryer) pleads to be let inside, but her skin is deformed from an infection. Howard urges Michelle not to let this woman in. The woman grows agitated and starts banging her head on the glass of the door.
Now fearing that Howard may be right, Michelle begins to listen to him. He apologizes for his previous behavior and admits to hitting her car. He then tells Michelle to stitch up the wound on his head from the broken bottle.
Eventually, the trio become friendlier with each other and start working together like a real family. Howard lets Michelle borrow clothes belonging to his daughter Megan, whom he lost. He shows Michelle a picture of Megan. Michelle and Emmett also bond, with Emmett discussing how he had a chance to play sports for a university, but he skipped the chance to leave town because he was afraid. Michelle recounts a time when she saw a little girl being abused by her dad at a hardware store, and she felt bad for walking away and doing nothing, especially considering her own troublesome childhood.
The air filtration system goes down, and only Michelle is small enough to fit through the vents and go to the filtration room. She resets the unit but notices a ladder leading to outside, just beneath a window. On the window is "HELP" scratched out, with the L and P having traces of blood on it. On the floor, Michelle finds two bloody earrings that she recognizes from the picture of Megan. She shows the picture to Emmett, who says the girl in the picture is really a girl from his high school named Brittany, and she went missing a while back. The two realize that Howard is a threat, and they need to get out of there.
Michelle and Emmett steal Howard's tools and start constructing a makeshift biohazard suit and gas mask. Howard discovers the stolen tools and brings out a vat of perchloric acid to dissolve them. Howard demands to know why they were trying to take his gun. Emmett speaks up and says he did it so that Michelle could respect him the way she respects Howard. Howard forgives Emmett and then shoots him in the head.
Michelle finishes the suit and tries to make her escape. Howard catches her, but she pushes the vat of acid toward him, causing him to slip and fall face-first onto it. She climbs over and heads toward the exit. The acid eats through an electrical wire and starts a fire. Howard follows Michelle and she pushes a shelf on top of him. She climbs through the vents to head to the filtration room. Howard stabs through the vents with a knife. He grabs onto Michelle as she makes it to the end, but she slams his hand hard enough for it to rip off. The fire starts spreading through the bunker. Michelle puts the suit and gas mask on and prepares to head on outside.
Once again, everything is calm. Michelle looks up and sees birds flying overhead. She takes off the mask and breathes in the fresh air. She goes to Howard's truck and then spots what she thinks is a helicopter in the distance. It's really a massive alien hovercraft. The bunker then explodes, attracting the alien spacecraft toward that spot. It begins to spread a toxic green gas, so Michelle quickly puts the mask back on. Michelle runs to the barn and finds the dead body of the infected woman from earlier. Through the cracks, Michelle sees a worm-like creature surrounding the truck. When it's gone, she grabs the cars keys off the woman and runs toward it. The creature chases Michelle, cornering her in the truck. The craft goes near her and picks the truck up, bringing it closer to its mouth. Michelle grabs a magazine, lighter, and whisky bottle to make a Molotov cocktail. She lights it and seizes the opportunity to throw it into the creature's mouth. It drops the truck and then explodes.
Michelle drives away for good. She hits Howard's mailbox, which has the address "10 Cloverfield Lane" on it. Michelle turns on the radio and hears that anybody seeking refuge from the alien attacks may head to Baton Rouge, but anybody with combat or medical expertise is needed in Houston. Michelle reaches the sign that directs people straight to Baton Rouge or left to Houston. Michelle makes the choice to go left. As she drives there, a thunderclap shows a bigger alien hovercraft hiding in the clouds.