An elderly Jesuit priest named Father Lankester Merrin is leading an archaeological dig in northern Iraq and is studying ancient relics. After discovering a small statue of the demon Pazuzu (an actual ancient Assyrian demigod), a series of omens alerts him to a pending confrontation with a powerful evil, which, unknown to the reader at this point, he has battled before in an exorcism in Africa.
Meanwhile, in Georgetown, a young girl named Regan MacNeil is living with her famous mother, actress Chris MacNeil, who is in Georgetown filming a movie. As Chris finishes her work on the film, Regan begins to become inexplicably ill. After a gradual series of poltergeist-like disturbances in their rented house, for which Chris attempts to find rational explanations, Regan begins to rapidly undergo disturbing psychological and physical changes: she refuses to eat or sleep, becomes withdrawn and frenetic, and increasingly aggressive and violent. Chris initially mistakes Regan's behavior as a result of repressed anger over her parents' divorce and absent father.
After several unsuccessful psychiatric and medical treatments, Regan's mother, an atheist, turns to a local Jesuit priest for help as Regan's personality becomes increasingly disturbed. Father Damien Karras, who is currently going through a crisis of faith coupled with the loss of his mother, agrees to see Regan as a psychiatrist, but initially resists the notion that it is an actual demonic possession. After a few meetings with the child, now completely inhabited by a diabolical personality, he turns to the local bishop for permission to perform an exorcism on the child.
The bishop with whom he consults does not believe Karras is qualified to perform the rites, and appoints the experienced Merrin—who has recently returned to the United States—to perform the exorcism, although he does allow the doubt-ridden Karras to assist him. The lengthy exorcism tests the priests both physically and spiritually. When Merrin, who had previously suffered cardiac arrhythmia, dies during the process, completion of the exorcism ultimately falls upon Father Karras. When he demands that the demonic spirit inhabit him instead of the innocent Regan, the demon seizes the opportunity to possess the priest. Karras heroically surrenders his own life in exchange for Regan's by jumping out of her bedroom window and falling to his death, regaining his faith in God as his last rites are read.