Harris was born Sherwin David Harris in Chicago, Illinois, the son of Mattie and John Harris. 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 was awarded the New York Film Festival's 1st Run Best Actor Award for his portrayal of "Derrick 'D-Train' Trainer" in Morningside Prep, a thirty minute short movie directed by rising filmmaker, Malcolm Lee. He 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 legendary Harlem drug kingpins.

He starred as Avon Barksdale in the first three seasons of HBO's original series The Wire. He also produced his own debut album, Beautiful Wonderful, which was intended for release in 2005. Harris returned to his role as the ruthless drug kingpin Avon Barksdale in the fifth and final season of The Wire.

He had previously appeared in a minor role as Correctional Officer in the HBO Series Oz who is sympathetic to the Muslim inmates, leaving a gun for them to use in an imminent riot at the end of Season 1.

In June 2008 director Martin Guigui revealed on his production blog that Harris was cast as Nate "Sweetwater" Clifton in Sweetwater, the movie about the first black player in the NBA.