Brother and sister Felice and Clare find themselves alone in a theatre during a tour or their play titled The Two-Character Play, a tour that seems to have gone on forever. The rest of the company has deserted them, leaving the siblings to perform alone.

Tennessee Williams uses the convention of a play within a play, the siblings erasing the separation between their own lives with the lives of the characters they portray, to explore the precarious relationship between the artist and the art. As the two characters weave in and out of reality, improvising and rewriting their lines, the audience also eventually abandons them in the theatre.

Williams draws from his own autobiographical details including his relationship with his real life, institutionalized sister Rose, and his own issues with substance abuse.