Although expansive in its prose, The Exorcist is a surprisingly concise novel with a limited cast of characters. The story begins and remains focused on the MacNeil household. The mother, Chris, is an actress inspired by Blatty's friend and former neighbor, Shirley MacLaine. (Following the overwhelming public response to the novel, Blatty regretted this choice, as some people believed Shirley MacLaine actually had a daughter who was possessed.) Despite Chris's profession, Blatty avoided the typical tropes of show-business novels; Chris is portrayed as down-to-earth, not sexually active, and primarily a devoted mother. One subplot, omitted from the film adaptation, shows Chris sacrificing a much-coveted chance to direct in order to care for her daughter. Regan, her daughter, is not as deeply developed because her personality is quickly overshadowed by the possession. Nevertheless, she shares her mother's cheerful disposition and concern, particularly over her parents' divorce, and is portrayed as intelligent and active.

The other three members of the household are staff: Willie and Karl Engstrom, an older couple who manage the home, and Sharon Spencer, a young woman who serves as Regan's tutor and Chris's social secretary. While realistic, these characters are more crucial to the plot than to the novel's themes. They all serve as objective witnesses to the signs of possession. Additionally, Karl becomes a prime suspect in the murder of Burke Dennings, which diverts suspicion away from another piece of evidence regarding Regan's condition.

Dennings, the flamboyant British director of the film Chris is starring in, adds color and humor to the book, ranging from genially obscene to wittily abusive, depending on his level of intoxication. In People magazine, Blatty mentions that Dennings is based "on a real-life director who used to be a bit of a drunk." Dennings' death is crucial to the detective aspect of the novel. After Burke's demise, the humor and color are provided by Detective William Kinderman, who resembles Columbo with his disheveled appearance, "schmaltz," and hidden brilliance. While much of Blatty is reflected in Karras, a significant portion of the author is also embodied in Kinderman, including musings about God and a dialogue style reminiscent of Blatty's other works.

The other two central characters are the exorcists. Though it may not be immediately apparent in either the novel or the movie, Father Karras and Father Merrin are almost perfect complementary opposites. Merrin, the seasoned exorcist, is confident in his faith but acknowledges his shortcomings in actively loving others. Karras, on the other hand, is deeply compassionate: he cares intensely for his mother, the priests seeking his psychiatric counsel, and eventually the MacNeil family, which draws him into the exorcism despite his profound skepticism about the supernatural.

Karras is physically robust—he resembles a boxer, jogs regularly, and participates in sports—but is susceptible to demonic manipulation of his repressed emotions, especially guilt. Conversely, Merrin is emotionally and spiritually resilient but conceals a physical weakness, a heart condition. An archaeologist by profession, Father Merrin is partly inspired by theologian and paleontologist Pierre Teilhard de Chardin, whom Blatty references in several of his works and interviews.

Among the minor characters are the physicians, a psychic who lends Chris a book on witchcraft and possession (but is otherwise notably absent from the story), and guests at a party Chris hosts, including an astronaut. Among the numerous Jesuit priests who serve as secondary characters, perhaps the most significant is Father Dyer, who believes that Father Karras regained his faith in the end and who later becomes friends with Kinderman.