He is best known for his breakout role as John Coffey in The Green Mile (1999), for which he was nominated for the Academy Award for Best Supporting Actor and other honors, and for playing Kingpin in Daredevil and Spider-Man: The New Animated Series (both 2003).

He also appeared in movies such as Armageddon (1998), The Whole Nine Yards (2000), Planet of the Apes (2001), The Scorpion King (2002), Sin City (2005), and Talladega Nights: The Ballad of Ricky Bobby (2006), as well as in the role of Leo Knox in the television series Bones (2011) and its spin-off The Finder (2012).

[3] He always wanted to act, but had to drop out of the communication program at Alcorn State University to support his family when his mother became ill.[4] Duncan's large frame—6 feet 5 inches (196 cm) and 315 pounds (143 kg)—helped him in his jobs digging ditches for Peoples Gas Company and as a bouncer at several Chicago clubs.

[6] In 1979, he participated in the Disco Demolition Night at Comiskey Park, home of the Chicago White Sox, where he was among the first 100 people to run onto the field and slide into third base.

During this time, he worked as a bodyguard for celebrities like Will Smith, Martin Lawrence, Jamie Foxx, LL Cool J, and The Notorious B.I.G., all the while doing bit parts in television and films.

[15] In 2009, he stopped eating meat and later appeared in a PETA ad campaign, touting the health benefits and his increased strength from a vegetarian diet.

His other voice roles include TV series such as Loonatics Unleashed and Operation: Z.E.R.O., Quiznos commercials, and a number of video games such as Demon Stone, SOCOM II U.S. Navy SEALs, The Suffering: Ties That Bind, Saints Row, Soldier of Fortune, and God of War II, where he provided the voice of the Titan Atlas.

[21][22] They also claimed that Omarosa manipulated Duncan in his final days, lied about their engagement, and sold his belongings without the family's knowledge.

[25] Duncan trained in Brazilian jiu-jitsu at the Gracie Academy in Torrance, California, and held a purple belt in the discipline.