The opera is through-composed, and set in the intensely CatholicLittle Italy of New York City in 1954. It follows Annina, a young and simple woman who is blessed with the stigmata. She often hears voices and has visions of the angels. Her brother, Michele, is an atheist who is intensely protective of his sister; he believes she requires hospitalization, but he cannot stop the rest of the neighborhood from believing her a saint.
The original set for The Saint of Bleecker Street was designed by the American symbolic realist painter George Tooker, and was based on elements from his painting The Subway, currently in the collection of the Whitney Museum of American Art.