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Lee studied filmmaking at both Morehouse College and the New York University Tisch School of the Arts, where he directed his student film Joe's Bed-Stuy Barbershop: We Cut Heads (1983), which won a Student Academy Award. He later founded the production company  40 Acres and a Mule Filmworks, where he has produced more than 35 films. He made his directorial debut with the comedy She's Gotta Have It (1986). He received widespread critical acclaim for the drama Do the Right Thing (1989), for which he was nominated for the Academy Award for Best Original Screenplay. He directed the historical epic Malcolm X (1992), earning the Golden Bear at the Berlin International Film Festival. With the biographical crime dramedy BlacKkKlansman (2018), he won the Academy Award for Best Adapted Screenplay and the Cannes Film Festival Grand Prix Award.

He has also written and directed films such as School Daze (1988), Mo' Better Blues (1990), Jungle Fever (1991), Crooklyn (1994), Clockers (1995), Bamboozled (2000), 25th Hour (2002), Inside Man (2006), Chi-Raq (2015), Da 5 Bloods (2020), and Highest 2 Lowest (2025). Lee has also acted in eleven of his feature films. He is also known for directing numerous documentary projects, including 4 Little Girls (1997), which was nominated for the Academy Award for Best Documentary Feature Film. He directed the HBO series When the Levees Broke (2006), which won two Primetime Emmy Awards for Outstanding Directing for a Documentary/Nonfiction Program and Exceptional Merit in Documentary Filmmaking. He also directed the HBO documentary If God Is Willing and da Creek Don't Rise (2010) and the David Byrne concert film American Utopia (2020).

Lee has received several honours, including the Honorary BAFTA Award in 2002, an Honorary César in 2003, the Academy Honorary Award in 2015, and the National Medal of Arts in 2023. Five of his films have been selected by the Library of Congress for preservation in the National Film Registry for being "culturally, historically, or aesthetically significant". He has received a Gala Tribute from the Film Society of Lincoln Center as well as the Dorothy and Lillian Gish Prize. His films have featured breakthrough performances from actors such as Denzel Washington, Laurence Fishburne, Samuel L. Jackson, Giancarlo Esposito, Rosie Perez, Delroy Lindo, John Turturro, and John David Washington.