An elderly Jesuit priest named Father Lankester Merrin is leading an archaeological dig in northern Iraq and studying ancient relics. Following the discovery of a small statue of the demon Pazuzu (an actual ancient Sumerian demigod) and a modern-day St. Joseph medal curiously juxtaposed together at the site, 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 living with her famous actress mother, Chris, becomes inexplicably ill. After a gradual series of poltergeist-like disturbances, she undergoes disturbing psychological and physical changes, appearing to become "possessed" by a demonic spirit.
After several unsuccessful psychiatric and medical treatments, Regan's mother turns to a local Jesuit priest. 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.
After consultation with the Jesuit president of Georgetown, the bishop appoints the experienced Merrin, recently returned to the States, to perform the exorcism and allows the doubt-ridden Karras to assist him. The lengthy exorcism tests the priests, both physically and spiritually. After the death of Merrin, the task ultimately restores Karras' faith, leading him to give his own life to save Regan's.