Born in Denmark to an Italian father and an African-American mother, Giancarlo Esposito lived in Europe, New York, and Cleveland until his family settled in Manhattan when he was six. He began acting in the late 1970s. Throughout most of the 1980s he appeared in small roles in films such as Maximum Overdrive and Trading Places and TV shows such as Miami Vice and Spenser: For Hire, until landing his breakout role as a conflicted, light-skinned college student in director Spike Lee's 1988 film School Daze. Over the next four years, Esposito and Lee collaborated in three other movies: Do the Right Thing, Mo' Better Blues, and Malcolm X.

Esposito is probably best known for his portrayal of Det. Mike Giardello on the TV crime drama Homicide: Life on the Street, a role he played from 1998 until the series' cancellation in 1999. Other TV credits include NYPD Blue, Law & Order, South Beach, and The Practice.

Esposito's career and choice of roles defies pigeonholing; he has portrayed drug dealers (Fresh), cops (The Usual Suspects), political radicals (Bob Roberts) and even a demonic version of the Greek God of Sleep from another dimension (Monkeybone.) He also appeared as Muhammed Ali's father in Ali and Nuyorican poet Miguel Pi񥲯's friend and collaborator Miguel Algarin in Pi񥲯, both released in 2001.