Note: the characters in this film are unnamed and are referred to by descriptors.
The film opens with a woman standing in the midst of crackling flames. Her flesh burns to a crisp as screams are heard in the background.
We then see a man, "Him" (Javier Bardem), place a crystal object in his bedroom. The house then changes from burnt and rundown to completely refurbished. A young woman, "Mother" (Jennifer Lawrence), materializes in his bed and calls out for Him, her husband. Mother walks through the house until she finds Him, and they kiss.
Him is a noted poet suffering from writer's block following the loss of his first wife. Mother is trying to paint one of the rooms in the house using different colors. She walks toward the wall and sees a vision of a beating heart within the walls.
Someone knocks on the couple's front door. Him welcomes the stranger, "Man" (Ed Harris), into his house. Him is polite toward Man, but Mother is not quite comfortable with his presence. Man was directed to the house under the impression that it was some kind of bed-and-breakfast. Him shows Man his office with his written works, and Man admits to being a fan of Him's work. Him spends most of the time chatting with Man, telling Mother it's nice to have someone to talk to who enjoys his work, despite Mother saying she loves his work too.. Still, she allows Man to stay. However, Man has violent coughing fits that Him tends to. Mother later sees Man puking in the toilet with Him standing over Man. Mother notices a chunk of flesh missing from Man's ribs, but Him covers it with his hand.
The next day, Mother asks Him how Man is doing. Man walks downstairs and says he feels wonderful. Moments later, another knock is heard at the door. Mother answers it to find Man's wife, "Woman" (Michelle Pfeiffer), at the front. Him welcomes her into the house as well. Him and Man go for a hike while Mother is left alone with Woman. She bothers Mother with questions about whether or not she and Him want children, as well as Woman's curiosity in going up to Him's office, but Mother says nobody can go in without his permission. Upon their return, Man has another coughing fit. Him explains to Mother that Man is dying, and he and his wife are big fans of Him, so they wanted to meet him before it was too late.
Man and Woman enter Him's office and accidentally shatter the crystal object. Him is devastated, ordering them out of the office. He holds the broken pieces in his hands, gripping them until he bleeds. Mother orders Man and Woman to leave, but they instead go into another room to get intimate. After a while, Man and Woman still have not left until Him and Mother both agree that they must leave.
As Man and Woman are getting ready to head out, their sons (Domhnall and Brian Gleeson) arrive, bickering over the state of their father's will. Oldest Son is angry at getting less than his brother. The confrontation turns violent as Oldest Son attacks his brother before Him separates them. They run into the bedroom where Oldest Son bludgeons his brother over the head, causing his skull to crack open and bleed. Him picks up Younger Brother and carries him to the hospital with Man and Woman following.
Mother cleans up the blood on the floor, but one stain in the floor won't come out. She presses against it and it starts leaking blood to the basement. Mother goes downstairs and sees blood leaking into a light bulb until it shatters. The sprayed blood forms around the wall. Mother breaks through and sees a furnace oil tank. Oldest Son appears from behind her, having been hiding. He simply takes something of his and leaves the house without a word.
When the others return, Him tells Mother that Younger Brother is dead. A wake is held for him in the house, with other strangers arriving to pay their respects. Mother becomes increasingly agitated with the behavior of the guests. She argues with Him over their stay until they begin to have passionate sex.
In the morning, Mother tells Him that she feels she is pregnant. Elated, Him is inspired to start writing again. He completes his work and sends it out, getting the attention of The Herald (Kristen Wiig).
Some time later, Mother is nearing the end of her pregnancy. As she cooks dinner to celebrate Him's written works, fans of Him start showing up at the house. One woman enters with her child who wet his pants. Mother goes to the bathroom and sees a man peeing in the sink. Soon, a horde of fans start walking up to the house, including The Herald, who wants to speak to Mother. Their growing presence starts to take a toll on Mother, who experiences a pain that causes the house to shake.
Despite Mother trying to hide from the crowd, the fans start to break things and steal stuff from the house. As she moves to different rooms, people begin to act violently toward one another. Some people are tied up and have bags over their heads. The Herald walks around casually shooting them in the head before calmly talking to Mother. A massive blast goes through the room, killing The Herald. A SWAT team has entered the house, fighting against the increasingly manic crowd of fans. It quickly becomes apparent that the fans are part of a pagan cult.
Mother starts to go into labor. Him brings her into his office where she gives birth to a baby boy. Him wants to hold his son, but Mother refuses to let him go. She demands that Him send the fans away. Mother sits in the office for a whole day holding her son until she falls asleep. When she wakes up, her baby is gone. Him brings their son to show to the crowd. They start passing the baby around, even as he pees on them. The crowd then breaks the baby's neck. Mother hears it and frantically tries running to the front of the room. When she gets there, she sees her baby has been horribly mutilated, and the fans are eating him. Mother screams in fury, causing the house's foundation to crack. She grabs a piece of glass and starts stabbing and slashing the fans, until their leader grabs her and whacks her over the head with a candlestick. The fans start brutally beating Mother and tearing her clothes off, calling her a whore and a bitch. Him runs in to stop them, holding his wife tearfully. Mother screams at Him that they killed their baby.
Mother runs to the basement where she comes upon the oil tank. She breaks it open and lets the oil flow out before taking out a lighter. Him pleads with Mother to not do anything, but she defies him and drops the lighter. The entire house goes up in flames, burning everyone in the house to ashes before everything around the house explodes. Him and Mother survive, but Mother is terribly burnt while Him is unscathed. Him carries Mother's body out of the basement. She asks Him who he is. He says his name is Eli. When she asks what he wants, he says he wants her love. She tells Him he can have it. He digs his hands into her chest and pulls out her heart, causing her body to crumble to pieces.
Him squeezes the heart to reveal another crystal object like the one he had before. He places it in the same spot in his office while chuckling to himself. The house once again turns from destroyed to brand new. A young woman then forms in the bed, calling out for her husband.