Her memoir, Becoming Maria: Love and Chaos in the South Bronx was published in 2015, and her works include the novel The Revolution of Evelyn Serrano as well as several children's books.

She is the creator of the animated children's television series Alma's Way, from Fred Rogers Productions, and serves as an executive producer, writer and voice actor for the show.

[10] She has also appeared in multiple films, including Death Wish, Firepower, Night Flowers, Wonder Woman in Cheetah on the Prowl, Sesame Street Presents: Follow That Bird, The Adventures of Elmo in Grouchland, The Guitar, Dumped!, Missing Grandma, and Godmothered, and television programs, including BJ and the Bear, Law & Order, and Law & Order: SVU.

She was featured in the Learning Leaders (volunteers helping students succeed) poster, designed to encourage reading in NYC public schools.

She also provided the voice-over narration in several animated segments in the English version of the Swedish television show Fem myror är fler än fyra elefanter.

[citation needed] On December 3, 2020, Deadline reported that Manzano would return to PBS to create a new animated children's television series titled Alma's Way.

[25] On May 1, 2016, she received the Lifetime Achievement Emmy Award from the National Academy of Television Arts and Sciences presented to her by Rita Moreno and Mario Lopez, with a special introduction by Lin-Manuel Miranda and a retrospective of her career on Sesame Street featuring a montage of clips of her most iconic moments including Maria's classic Charlie Chaplin routine, her marriage to Luis, the birth of her daughter Gabi, coping with the death of Mr. Hooper, and appearances by fellow cast and guests including Emilio Delgado, Bob McGrath, Alan Muraoka, Loretta Long, Big Bird, Rosita, Elmo, and Sonia's real life friend Supreme Court Justice Sonia Sotomayor.