Born in Miami, Florida, Harry was adopted as an infant and raised in Hawthorne, New Jersey. After attending college, she worked various jobs, including as a secretary, dancer, and Playboy Bunny, before breaking through in the music industry. Harry co-formed Blondie in 1974 in New York City. The band released their eponymous debut album in 1976, and released a further three albums between then and 1979, including Parallel Lines, which spawned six singles, including "Heart of Glass". Their fifth record, Autoamerican (1980), afforded Harry and the band further attention, spawning such hits as a cover of "The Tide Is High", and "Rapture", the latter of which is considered the first rap song to chart at number one in the United States.

In 1981, Harry released her debut solo album, KooKoo, and, during a hiatus of Blondie, embarked on an acting career, appearing in lead roles in the neo-noir Union City (1980) and in David Cronenberg's body horror film Videodrome (1983). She released her second solo album, Rockbird, in 1986, and subsequently starred in John Waters's cult dance film Hairspray (1988). Harry went on to release two more solo albums between then and 1993, after which she returned to film with roles in a John Carpenter-directed segment of the horror film Body Bags (1993), and in the drama Heavy (1995).