Sister Mary Ignatius... was first performed on December 14, 1979, at the Ensemble Studio Theatre in New York City. It was performed on a bill with one-act plays that included works by David Mamet, Marsha Norman, and Tennessee Williams. Durang, who was raised a Roman Catholic, won an Obie Award for the play as did Elizabeth Franz for her role as Sister Mary Ignatius.
In 1981, the play was presented again, this time on a double bill with a new Durang one-act, The Actor's Nightmare. Elizabeth Franz repeated her acclaimed performance as Sister Mary, and in The Actor's Nightmare, she played the glamorous Sarah Siddons. Jeff Brooks played the accountant in that play who shows up at a theatre and is told he is the understudy and must go on; and in Sister Mary, he played the troubled alcoholic ex-student Aloysius. Others in the cast included Polly Draper, as Diane. the emotionally wounded girl who threatens Sister's life, Mary Catherine Wright as Philomena, the unwed mother, Timothy Landfield as Gary, the polite gay one, and young Mark Stefan as little Thomas. The double bill — featuring Sister Mary — was presented at Playwrights Horizons in New York City and was directed by Jerry Zaks. It was a critical success and moved to off-Broadway where it ran for two and a half years. As the run went on, other actresses took over the role of Sister: Nancy Marchand, Kathleen Chalfant, Mary Louise Wilson, Lynn Redgrave, and Patricia Gage.
In Los Angeles, Elizabeth Huddle and then Lynn Redgrave played Sister Mary. Thomas was played alternately by seven-year-old Chad Allen and 10-year-old Shane Butterworth. In San Francisco, Sister Mary was played by Cloris Leachman, Lynn Redgrave and Peggy Cass. Thomas was played by eight-year-old Solomon Cheifer. In Los Angeles, the play was revived in 2004 at the ARK Theatre Company in a production directed by Susan Lee Johnson.