Guare's early plays, mostly comic one-acts exhibiting a flair for the absurd, include To Wally Pantoni, We Leave a Credenza, produced at Caffe Cino in 1965 and Muzeeka (1968).
Cop-Out premiered on Broadway at the Cort Theatre on April 7, 1969, and closed on April 12, 1969, as part of two one-act plays, including Home Fires. Cop-Out starred Linda Lavin and Ron Leibman.
The House of Blue Leaves, a domestic black comedy, premiered Off-Broadway in 1971 at the Truck and Warehouse Theatre. It was revived off-Broadway at the Lincoln Center for the Performing Arts in 1986 before transferring to Broadway later in 1986. The play was revived on Broadway in 2011, starring Ben Stiller, whose mother, Anne Meara, had appeared in the 1971 production. According to Marilyn Stasio writing in Variety the play "sets the bar for smart comic lunacy."
Chaucer in Rome, "said to be a sequel of sorts to ... The House of Blue Leaves and includ[ing] the son of one of the earlier play's characters" received its world premiere at the Williamstown Theatre Festival in July 1999 and was produced Off-Broadway in 2001 at Lincoln Center Theater's Newhouse Theater.
Later plays include Marco Polo Sings a Solo, produced at the Joseph Papp Public Theater/New York Shakespeare Festival in January to March 1977, with a cast that featured Joel Grey, Anne Jackson, Madeline Kahn, and Sigourney Weaver. Bosoms and Neglect was produced on Broadway in 1979, and revived off-Broadway in 1998 by the Signature Theatre Company. Moon Over Miami was produced at the Williamstown Theatre Festival in 1987 and then at the Yale Repertory Theatre in New Haven in February 1989.
Guare's cycle of plays on nineteenth-century America are: Gardenia (1982) Lydie Breeze (1982) and Women and Water (1985). The so-called Lydie Breeze series, also called the "Nantucket" series, "follows a group of idealistic 19th century characters and their attempts to create a utopian society. "
Six Degrees of Separation was originally produced off-Broadway by Lincoln Center Theater at the Mitzi E. Newhouse Theater in June 1990. Six Degrees of Separation is an intricately plotted comedy of manners about an African-American confidence man who poses as the son of film star Sidney Poitier. It has been the most highly praised and widely produced of Guare's full-length plays. It was made into a film in 1993, starring Stockard Channing and Will Smith.