An American actor, writer and director. He was born in Brooklyn, New York, the son of Dorothy, who worked as a hostess at Howard Johnson's, and John Buscemi, a sanitation worker and Korean War veteran. Buscemi's father was Sicilian American and his mother Irish American. He has three brothers: Jon, Ken, and Michael. Buscemi was raised Roman Catholic.

Buscemi has starred and supported in successful Hollywood and indie films, including Parting Glances (1986), New York Stories (1989), Mystery Train (1989), Reservoir Dogs (1992), Pulp Fiction (1994), Desperado (1995), Con Air (1997), Armageddon (1998), The Grey Zone (2001), Ghost World (2001), Big Fish (2003), Lean on Pete (2017), and The Death of Stalin (2017). He is also known for his appearances in many films by Coen brothers: Miller's Crossing (1990), Barton Fink (1991), The Hudsucker Proxy (1994), Fargo (1996), and The Big Lebowski (1998). Buscemi provides the voice of Randall Boggs in the Monsters, Inc. franchise.

From 2010 to 2014, he portrayed Enoch "Nucky" Thompson in the critically acclaimed series Boardwalk Empire, which earned him two Screen Actors Guild Awards, a Golden Globe, and two nominations for an Emmy Award. He made his directorial debut in 1996, with Trees Lounge, in which he also starred. Other works include Animal Factory (2000), Lonesome Jim (2005), and Interview (2007).

Buscemi has one son, Lucian, with his wife Jo Andres.