Manzano broke the news during a speech at the annual conference for the American Library Association, which shared the news on Twitter. She joined Sesame Street in 1971 and was promoted to a series regular three years later.
On the show, Manzano plays Maria, who runs the Fix-It Shop with her on-screen husband Luis (Emilio Delgado). Over the years, Maria has shared screen time with most of the Sesame Street characters, forging a particularly special bond with Oscar the Grouch.
She was nominated for two Emmy Awards for playing Maria, and has won 15 Emmys as a writer for Sesame Street.
Manzano's memoir, Becoming Maria: Love and Chaos in the South Bronx, is scheduled to be released in August.
What are some of your favorite Maria memories from Sesame Street? Will the show be the same without her?