Jackie Harry began acting after deciding that being a high school history teacher was not her calling. She studied acting at the Henry Street Settlement on the Lower East Side in New York City and began her career on the New York stage.

In 1978, she made her first professional acting debut as a chorus girl in the off-Broadway production of A Broadway Musical. She continued to appear in performances on and off Broadway, such as Eubie! and The Wiz. From 1983 to 1986, she played the role of Lily Mason on the daytime soap Another World, acting alongside other African Americans such as Petronia Paley, Michele Shay and a then-unknown Morgan Freeman. In 2003, she was the surprise guest on the Another World Reunion that SOAPnet coordinated and aired. She appeared at former co-star and close friend Linda Dano's request.

In 1985, she gained recognition playing neighborhood vamp Sandra Clark on the sitcom 227, a role for which she received an Emmy in 1987. Harry was the first African American to win an Emmy for the role of supporting actress in a sitcom (Gail Fisher had won an Emmy for supporting actress in a drama back in 1970).

She continued her career appearing in more movies and stage performances. In 1994, she gained more recognition as Lisa Landry, the single mother of Tia Mowry on the sitcom Sister, Sister (1994-1999).

In 2005, she appeared on VH1's Celebrity Fit Club 2, losing 39 pounds total after 100 days. She also recently starred in an episode of the sitcom Everybody Hates Chris.