Theater director Caden Cotard (Hoffman) is mounting a new play. His life catering to suburban blue-hairs at the local regional theater in Schenectady, New York is looking bleak. His wife Adele (Keener) has left him to pursue her painting in Berlin, taking their young daughter Olive (Goldstein) with her. His therapist, Madeleine Gravis (Davis), is better at plugging her best-seller than she is at counseling him. A new relationship with the alluringly candid Hazel (Morton) has prematurely run aground. And a mysterious condition is systematically shutting down each of his autonomic functions, one by one.

Worried about the transience of his life, he leaves his home behind. He gathers an ensemble cast into a warehouse in New York City, hoping to create a work of brutal honesty. He directs them in a celebration of the mundane, instructing each to live out their constructed lives in a growing mockup of the city outside. The years rapidly fold into each other, and Caden buries himself deeper into his masterpiece, but the textured tangle of real and theatrical relationships blurs the line between the world of the play and that of Caden's own deteriorating reality.