Guare was born in New York City and raised in Jackson Heights, Queens. He was raised a Roman Catholic, but now seems to be lapsed [1]. He was educated at Georgetown University, (BA, 1960), where in 1958 he contributed a song to an original musical revue entitled The Natives Are Restless and presented by the Mask and Bauble Dramatic Society. The song humorously attributed the success of many famous people to the syllable “O” in their names. Under the direction of Donn B. Murphy, his play The Toadstool Boy, about a country singer's quest for fame, won first place in the District of Columbia Recreation Department's One-Act-Play competition. In 1960, the Mask and Bauble presented The Thirties Girl, a musical for which Guare did the book, much of the music and the lyrics, again under Murphy's tutelage. Set in Hollywood's turbulent 1920's, it dealt with the dethronement of a reigning diva by a fresh-faced starlet. (Management of identity and celebrity, and the quest for fame, the focus of these early efforts, are recurring themes in the body of Guare's work. He subsequently imported the Hollywod ingenue's song, I'm Here With Bells On into his first full-length Off-Broadway play, The House of Blue Leaves, which received an Obie Award and New York Drama Critics Circle Award for Best American Play, and subsequently won Guare a Tony Award in its 1986 Broadway revival.)He then went to the Yale School of Drama, (MFA, 1963). His early plays, mostly comic one-acts exhibiting a flair for the absurd, include To Wally Pantoni, We Leave a Credenza (1964), Muzeeka (1968), and Cop-Out (1968). The House of Blue Leaves (1971), a domestic drama by turns wildly comic and despairingly desperate, moved Guare into the front ranks of American dramatists. Chaucer in Rome, a sequel to The House of Blue Leaves, received its world premiere at the Williamstown Theatre Festival in July 1999 and later enjoyed a production in New York by Lincoln Center Theater.

Later plays include Marco Polo Sings a Solo, Bosoms and Neglect, Moon Over Miami, Six Degrees of Separation, and Four Baboons Adoring the Sun. Lake Hollywood and A Few Stout Individuals (2002) both received their world premieres at Signature Theatre. Six Degrees of Separation (1990), an intricately plotted comedy of manners about an African-American confidence man who poses as the son of film star Sidney Poitier, has been the most highly praised and widely produced of Guare's full-length plays. It was made into a film in 1993.

Guare’s cycle of plays on nineteenth-century America, Gardenia, Lydie Breeze and Women and Water, has been performed in New York, Los Angeles, Chicago, San Francisco, Washington D.C., London and Australia. A Few Stout Individuals returns to nineteenth century America, with a cast that includes Ulysses S. Grant, Mark Twain, soprano Adelina Patti and the Emperor and Empress of Japan. These historic dramas investigate the violence at the root of American identity and the failure of utopian aspirations.

Guare has also been involved with musical theatre. His libretto with Mel Shapiro for the musical Two Gentlemen of Verona was a success when it premiered in 1971 and was revived in 2005 at the Public Theater's Shakespeare in the Park. It won the two men the Drama Desk Award for Outstanding Book of a Musical. He wrote the songs for Landscape of the Body. Guare wrote narration for '"Psyche,"' a tone poem by César Franck, which premiered at Avery Fisher Hall in October of 1997, conducted by Kurt Masur with the New York Philharmonic. In 1999, he revised the book of the Cole Porter musical comedy, Kiss Me, Kate for its Broadway revival. He also wrote the book for the Broadway musical Sweet Smell of Success.

Guare wrote the screenplay for Louis Malle's film Atlantic City (1980), for which he was nominated for an Oscar.

He was a founding member in 1965 of the Eugene O'Neill Theatre Center in Waterford, Connecticut and Resident Playwright at the New York Shakespeare Festival in 1976. He is a council member of the Dramatists Guild, co-editor of the Lincoln Center Theater Review, co-produces the New Plays Reading Room Series at the Lincoln Center Library for the Performing Arts and teaches in the Playwriting department at the Yale School of Drama.