The Boondocks began in 1996 as a webcomic on Hitlist.com, one of the first online music websites. At the time, he was also a DJ on The Soul Controllers Mix Show on WMUC. The Bookdocks also briefly appeared as a comic strip in the University of Maryland's newspaper The Diamondback during Jayson Blair's tenure as editor-in-chief. McGruder signed a deal with the Universal Press Syndicate and in April 1999, the strip began appearing in 160 newspapers.

McGruder's strip was a veritable lightning rod for criticism since it debuted in 1999, with newspapers consigning it to editorial sections, or suspending the run of the strip altogether. Favored targets of The Boondocks include BET, Condoleezza Rice, Whitney Houston, Bill Cosby, Vivica A. Fox, and black conservative commentator Larry Elder.

McGruder said in a 2002 keynote address at the July 12–14, 2002 H2K2 conference that he believed that President George W. Bush was involved with the September 11 attacks:

He visited Cuba, meeting Fidel Castro with California Rep. Barbara Lee. Later, during a 2003 reception hosted by The Nation, McGruder offended many attendees by defiantly expressing his support for Ralph Nader's 2000 presidential bid. McGruder endured heckling and walkouts as he defended his commitment to left-wing causes, including, he claimed, calling Condoleezza Rice a "mass-murderer" to her face during the 2002 NAACP Image Awards. In 2009, it was reported by the Richmond, Indiana publication Palladium Item that he had told a Martin Luther King Day audience at Earlham College in Indiana that then-President-elect Barack Obama was not black. McGruder released a statement insisting he was misquoted, while maintaining he remained "cautiously pessimistic" about Obama's presidency.

With Reginald Hudlin, McGruder co-authored a graphic novel, Birth of a Nation: A Comic Novel (2004), about African Americans in East St. Louis during an election. The book's illustrations were drawn by Cartoonist Kyle Baker.

By 2005 and as of 2013, McGruder was residing in Los Angeles with his three dogs: Remix, Retro, and Hooligan.

In 2010, McGruder worked as Screenwriter in the final treatment of the feature film Red Tails, released in early 2012. Its story is based on the Tuskegee Airmen, a group of African American combat pilots during World War II.

McGruder expressed interest in 2013 about filming a movie featuring The Boondocks TV series supporting character Uncle Ruckus. Gary Anthony Williams would reprise his role. McGruder set a goal of $200,000 for startup donations at uncleruckusmovie.com between January 30 through March 1, 2013, but the campaign ended with 2,667 backers and $129,963.

In March 2014, The Boondocks was revived for a new season, but without McGruder's involvement as its showrunner. The first episode of this final season was first broadcast on April 21, 2014.

In August 2017, it was announced that McGruder, along with Producer Will Packer, will develop a series for Amazon Video called Black America which will be based on an alternative history where emancipated black Americans receive 3 Southern states as reparations for slavery. It is reportedly seen as a response to HBO's alternative history series Confederate, whose plot entails a history where the Confederacy won the Civil War.