Derek Luke earned most of his $5 million net worth from his film and television projects. His 2002 debut film titled Antwone Fisher won him the Independent Spirit Award.

Luke starred as one of the 4 male leads in the war film Miracle of St. Anna which was produced by Spike Lee in 2008.  She is Alicia Key's special love interest in the singer's "Teenage Love Affair" music video. He played James 'Boobie' Miles in Friday Night Lights film and Sean "Puffy" Combs in Notorious (2009). In 2011, he played the role of Gabe Jones who was one of the members Captain America's Howling Commandos. Since June 2011, Luke plays the role of  an assistant surgeon as Miles Bourdet in HawthoRNe, a medical drama series.