The daughter of Puerto Rican parents, Manzano attended the High School of the Performing Arts in New York City and received a scholarship to attend Carnegie-Mellon University. While a drama student at Carnegie-Mellon, Manzano appeared in the original off-Broadway production of Godspell in New York. In 1972 she created the role of Maria Rodriguez, a shopkeeper and mother on Sesame Street, the popular children's TV program. As one of the show's writers, Manzano has shared in the seven Emmy awards the program has won for writing. She has also received an Emmy nomination for Best Performer in a Children's Program. Manzano has appeared in the plays The Living Room and Happy New Year, and directed and starred in Appearing in Person Tonight: Your Mother. She has had parts in the films Death Wish, Firepower, and Night Flowers. Manzano is also active in experimental theater. In 1986 she married Richard Reagan. They have one daughter.