Deborah Harry was adopted when she was three months old by a family from Hawthorne, New Jersey, and attended Hawthorne High School, where she graduated in 1963. Prior to starting her singing career she moved to New York in the late 1960s and worked as a secretary at the BBC Radio New York office for one year. Later, she was a waitress at Max's Kansas City, and worked in a Dunkin' Donuts, after which she was a dancer in Union City, and a Playboy Bunny.

She began her musical career with a folk rock group, the Wind in the Willows. Harry then joined a girl-group trio, The Stilettos, in the early 1970s. The Stilettos' backup band included her eventual boyfriend and Blondie guitarist, Chris Stein. Harry and Stein formed the band Blondie in the mid-1970s, naming it for the wolf whistle men often yelled at Harry from passing cars. Blondie quickly became regulars at Max's Kansas City and CBGB's in New York City. After a debut album in 1976, commercial success followed in the late 1970s and early 1980s, first in Australia and Europe, then in the United States.

With her two-tone bottle-blonde hair, Debbie Harry quickly became a recognizable icon of punk style. Her look was further popularized by the band's early presence in the music video revolution of the era. She was a continued regular at Studio 54 and was associated with Andy Warhol. The clip for 'Rapture' appeared within the first 24 hours of MTV's launch. Harry's strong stage persona of cool sexuality and streetwise style became so closely associated with the group's name that many came to believe the singer's name to be "Blondie". The difference between the individual Harry and the band Blondie was famously highlighted with a "Blondie is a Group" button campaign by the band in 1979. To complicate matters further, Harry sometimes described her character in the band as being named "Blondie.

Through 1976 and 1977, Blondie released their first two albums to varying success outside the US. However, 1978's Parallel Lines shot the group to huge international success, and included the smash hit single "Heart of Glass". The release of Eat to the Beat in 1979 and Autoamerican in 1980 continued the band's run of hits, including "Atomic", "The Tide Is High", "Rapture" and the #1 single "Call Me" from the film soundtrack American Gigolo.

After a year long hiatus in 1981 during which Harry released her first solo album, Blondie regrouped and released their sixth studio album The Hunter, which featured the U.S. and UK hit single "Island of Lost Souls" and the minor UK hit "War Child".

After a final tour of Europe with The Jazz Passengers in the summer of 1998, Deborah Harry resumed duties as lead vocalist of Blondie. Prior to the release of No Exit, the lead single "Maria" debuted at number one in the UK, giving Blondie their sixth UK no.1 hit. "Maria" also reached #1 in 14 different countries, the top 10 on the US Dance Charts, and Top 15 on the US Adult Top 40 Charts.

Harry entered the Guinness World Book of Records in 1999 as the "Oldest Female Singer to Reach No. 1 in the UK Chart" when Blondie went to number one with "Maria" on February 13, 1999 at the age of 53 years and 227 days.

To date, Harry has released five solo albums. Harry began her solo career with the album Koo Koo in 1981. It was certified gold in the US and Silver in the UK. In 1986, Harry released her second solo album Rockbird, which has been certified Gold by the BPI in UK. Her next solo venture was the album Def, Dumb and Blonde in 1989. At this point Harry reverted from "Debbie" to "Deborah" for her professional name. The first single "I Want That Man" was a big hit in Europe, Australia, and on the U.S. Modern Rock Charts.

Deborah Harry's fourth solo album, Debravation, appeared in July 1993. The album's first single was "I Can See Clearly", which peaked at #23 in the UK and #2 on the U.S. dance charts.

In 2006, Deborah Harry started work in New York City on tracks for her fifth solo album Necessary Evil (2007). Harry joined Cyndi Lauper's True Colors Tour 2007 for the Human Rights Campaign.

Some of Harry's notable film roles are appearances in Wild Style, Videodrome (1983); Union City (1980); New York Beat (otherwise known as Downtown '81, in which she plays the angel of the East Village alongside Jean-Michel Basquiat); Rock & Rule (1983), an animated movie where she did vocals; and Tales from the Darkside: The Movie (1990). She also had notable roles in such films as Spun, Cop Land, Heavy and My Life Without Me, and is featured in David Munro's feature film Full Grown Men.