In modern-day Georgetown, actress Chris MacNeil is living on location with her 12-year-old daughter Regan, where Chris has just wrapped the final scene of a film about student activism directed by her friend and associate Burke Dennings. After playing with a Ouija board and contacting a supposedly imaginary friend whom she calls Captain Howdy, Regan begins acting strangely, including making mysterious noises, stealing, constantly using obscene language, and exhibiting abnormal strength. Chris hosts a party, only for Regan to come downstairs unannounced, telling one of the guests, who is an astronaut, "You're gonna die up there", and then urinating on the floor. Later, Regan's bed begins to shake violently, adding further to her mother's horror. Chris consults a number of physicians, but Dr. Klein and his associates find nothing physiologically wrong with her daughter, despite Regan undergoing a battery of diagnostic tests.
One night when Chris is out, Burke Dennings is babysitting Regan, only for Chris to come home to hear he has died falling out the window. Although this is assumed to have been an accident, given Burke's history of heavy drinking, his death is investigated by Lieutenant William Kinderman, who interviews Chris, as well as priest and psychiatrist Father Damien Karras, who has recently been emotionally shaken after the death of his frail mother.
The doctors, thinking that Regan's aberrations are mostly psychiatric in origin, recommend an exorcism to be performed. Chris arranges a meeting with Karras. After recording Regan speaking backwards and witnessing the apparent effect of the scarification of her flesh with the words "Help Me" on her stomach, Karras is convinced Regan is possessed. Believing her soul is in danger, he decides to perform an exorcism. The experienced Merrin is selected for performing the actual exorcism with Karras present to assist.
Both priests witness Regan perform a series of bizarre, vulgar acts, and confine her to her bedroom. They attempt to exorcise the demon, but a stubborn Pazuzu toys with them, especially Karras. Karras shows weakness, and is dismissed by Merrin, who attempts the exorcism alone. Karras enters the room and discovers Merrin has died of a heart attack. After failing to revive Merrin, the enraged Karras confronts the mocking, laughing spirit of Pazuzu, tackling the demon to the ground. At Karras's furious demand, Pazuzu then possesses Karras, leaving Regan's body. In a moment of self-sacrifice, the priest throws himself out of the window before allowing Pazuzu to compel him to harm Regan, and is himself mortally injured. Father Dyer, an old friend of Karras, happens upon the scene and administers the last rites to his friend.
A few days later, Regan, who is now back to her normal self, prepares to leave for Los Angeles with her mother. Although Regan has no apparent recollection of her possession, she gives Father Dyer a kiss on the cheek. Kinderman, who narrowly misses their departure, befriends Father Dyer as he investigates Karras's death.
