Theater director Caden Cotard finds his life unraveling. He suffers from numerous physical ailments and has been growing increasingly alienated from his artist wife, Adele. He hits bottom when Adele leaves him for a new life in Berlin, taking their four-year-old daughter, Olive, with her.
After the success of his production of Death of a Salesman, Caden unexpectedly receives a MacArthur Fellowship, giving him the financial means to pursue his artistic interests. He determines to use it to create an artistic piece of brutal realism and honesty, into which he can pour his whole self. Gathering an ensemble cast into an enormous warehouse in Manhattan's Theater District, he directs a celebration of the mundane, instructing the cast to live out their constructed lives. As the mockup inside the warehouse grows increasingly mimetic of the city outside, Caden continues to seek solutions to his personal crises. He is traumatized as he discovers Adele has become a celebrated painter in Berlin and Olive is growing up under the questionable guidance of Adele's friend Maria. After a failed attempt at a fling with Hazel (the woman who works in the box office), he marries Claire, an actress in his cast, and has a daughter with her. Their relationship fails, and he continues his awkward relationship with Hazel, who is now married with children and working as his assistant. Meanwhile, an unknown condition is systematically shutting down his autonomic nervous system.
As the years rapidly pass, the continually expanding warehouse is isolated from the deterioration of the city outside. Caden buries himself ever deeper into his magnum opus, blurring the line between reality and the world of the play by populating the cast and crew with doppelgängers. For instance, Sammy Barnathan is cast in the role of Caden in the play after Sammy reveals that he has been obsessively following Caden for 20 years, while Sammy's lookalike is cast as Sammy. Sammy's interest in Hazel sparks a revival of Caden's relationship with her, leading Sammy to commit suicide. Shortly after Caden and Hazel finally get together, Hazel dies of smoke inhalation in her constantly burning house.
As he pushes against the limits of his personal and professional relationships, Caden lets an actress take over his role as director and takes on her previous role as Ellen, Adele's custodian. He lives out his days in the model of Adele's apartment under the replacement director's instruction while some unexplained calamity occurs in the warehouse leaving ruins and bodies in its wake. Finally, he prepares for death as he rests his head on the shoulder of an actress who had previously played Ellen's mother, seemingly the only person in the warehouse still alive. As the scene fades to gray, Caden begins to say that now he has an idea of how to do the play, when the director's voice in his ear cuts him off with his final cue: "Die."
