Manzano announced her plans to quit the long-running show at the American Library Association Annual Conference, reported Variety.
Manzano first appeared on "Sesame Street" in 1971, and became a series regular in 1974.
Manzano, with TV-husband Luis, are known to "Sesame Street" viewers for running the Fix-It Shop, which specializes in toaster repair.
Along with acting on the show, Manzano also served as a writer. She won 15 Emmys for her writing work on the show, and was nominated twice for her acting. Manzano also has a memoir releasing soon, "Becoming Maria: Love and Chaos in the South Bronx."