Jones was born in Mobile, Alabama, on April 10, 1968. His father was a professional baseball player in the Philadelphia Phillies organization. He moved to Mauldin, South Carolina, when he was a teen and graduated from Mauldin High School in 1985. One of his early acting experiences involved playing a werewolf in a haunted house to help raise money for the junior/senior prom. Jones enrolled in the College of Charleston, South Carolina. He left in 1990 without finishing his degree.

He scored his first Hollywood job in 1987, writing for the NBC comedy A Different World, on which he had a small guest role in the season five finale. During 1991-92, Jones penned the Fox series Roc and, in 1993, he co-produced The Sinbad Show. He also made a brief appearance on the FOX sitcom Herman’s Head in 1992.

Jones has been featured in many voice acting projects over the years. In 1993, Jones appeared in Yuletide in the ‘hood and in 1998, he made a guest appearance in the animated comedy TV Series, King Of The Hill. More recently, he lent his voice to the TV series Father of the Pride and the video games Halo 2 as the marine Sergeant Banks as well as other black marines and L.A. Rush. In 2006, he co-created, produced and voice acted for the MTV2 animated series The Adventures of Chico and Guapo.

After hosting Fox’s music series Sound FX, in 1994, Jones became one of the original nine cast members of MADtv. Unlike some of his fellow original repertory performers on MADtv, Jones came to the show with limited sketch comedy experience.

This exposure led to a plethora of opportunities for Jones. First, he hosted an HBO First Look special in 2000 and then, in 2003, was given his own late night talk show on FX called The Orlando Jones Show. Although his talk show was short lived, Jones continued to make additional television appearances. In 2003, he appeared on The Bernie Mac Show and on Girlfriends. In 2006, Jones decided to return to television as one of the lead characters of ABC’s crime drama The Evidence, as Cayman Bishop. He has also appeared in two episodes of Everybody Hates Chris, the first in 2007 as Chris’s substitute teacher and the second in 2008 as Clint Huckstable, an allusion to the character Cliff Huxtable played by Bill Cosby on The Cosby Show.

During the 2000s, Jones’ career began to branch out. In addition to his witty appearances in the 7-Up campaigns, Jones played the role of Clifford Franklin in The Replacements (2000) and the horror film From Dusk till Dawn 3: The Hangman’s Daughter (2003). In 2002, Jones landed the lead role of Daryl Chase in the action-dramedy Double Take (2001), alongside Eddie Griffin, and worked with David Duchovny, Seann William Scott and Julianne Moore in Ivan Reitman’s sci-fi comedy, Evolution (2001). Jones was also in the 2009 film Cirque du Freak: The Vampire’s Assistant and he appeared as the computer Vox 114 in The Time Machine (2002). His other more recent films includes Biker Boyz (2003), Godzilla (2005), Runaway Jury (2003) and Primeval (2004). Jones appeared in an uncredited cameo and played in Grindhouse Planet Terror (2007 film).

After two seasons on MADtv, Jones left the show to pursue a movie career. However, Jones returned to MADtv in 2004 to celebrate its 200th episode.

In 2008, he appeared as Harold Wilcox, a violent veteran with PTSD, on New Amsterdam. In the first season of the show, Jones also starred on Wild ‘N Out. Jones was the first guest star on the show. Jones was the co-host of ABC’s Crash Course (which was canceled after 4 episodes). On November 16, 2009, it was announced on TV Guide that Jones had been cast as Marcus Foreman, Eric Foreman’s brother on House, appearing in the season six episode “Moving the Chains”. In 2013, he was hired as a principal actor in the FOX television series Sleepy Hollow. The freshman drama opened to FOX’s highest fall drama premiere numbers since the premiere of ’24’ in 2001.

Jones married former model Jacqueline Staph in 2009. They have a daughter. In October 2011, Jones provoked controversy when he joked on Twitter that someone should kill former Governor of Alaska and Vice Presidential candidate Sarah Palin. He apologized for the comment several days later.

In 2011 Jones appeared in the documentary film Looking for Lenny, in which he talks about Lenny Bruce and freedom of speech. In 2012, Jones starred in Joe Penna’s original interactive thriller series Meridian created in conjunction with Fourth Wall Studios.

From 2016 through 2019, Jones portrayed Mr. Nancy, aka the African god Anansi, in the Starz series American Gods.