Harris was born in Chicago, Illinois, the son of Mattie, a housewife, and John Harris, a bus driver. He holds a Bachelors of Arts in Theater Arts from Northern Illinois University (NIU) and a Master of Arts from New York University.He is the younger brother of actor Steve Harris.
While enrolled in NYU, Harris starred in his first major film role in the basketball drama Above the Rim, starring opposite Tupac Shakur, and appeared in many theatrical stage productions of various off-Broadway plays. Harris subsequently guest-starred in a variety of television and film venues before portraying legendary rock guitarist Jimi Hendrix in Showtime's 2000 movie, Hendrix.
Later that year, Harris received his first NAACP Image Award nomination for "Outstanding Supporting Actor in a Motion Picture" along with the Blockbuster Movie Award nomination for "Favorite Supporting Actor in a Motion Picture" for his role as Julius "Big Ju" Campbell in Remember The Titans. In 2002, he starred in the Dame Dash produced cult-classic film, Paid in Full, based on the true story of three Harlem drug dealers with Harris playing the real-life kingpin, Azie Faison.
He starred as Avon Barksdale, loosely based on the real-life Nathan Barksdale, in the first three seasons of HBO's original series The Wire, as well as one episode in the fifth season. He also produced his own debut album, Beautiful Wonderful, which was intended for release in 2005.
In June 2008 director Martin Guigui revealed that Harris was cast as Nate "Sweetwater" Clifton in Sweetwater, a movie about the first black player in the NBA. As of April 2013, it is still in production.
In 2009 Harris had a major role in the film Just Another Day, where he played a successful rapper named A-maze. The film is about the clash between a young up-and-coming rapper and an older one at the top of his game. Incidentally, the younger rapper was portrayed by Jamie Hector, whose character Marlo Stanfield had a similar role in The Wire, with respect to Harris's character.
In 2012, Harris narrated the ESPN 30 for 30 film Benji. In the same year he also played Harold "Mitch" Mitchell in the Broadway revival of A Streetcar Named Desire by Tennessee Williams; alongside Blair Underwood, Nicole Ari Parker, and Daphne Rubin-Vega.