The Hudlins attended Katherine Dunham's Center for the Performing Arts, an experimental school, Warrington for high school and Reginald for after school martial arts classes. Hudlin has said that the experience was formative, and led to his older brother attending Yale University, and his attending Harvard University. In 1979, Hudlin graduated from Assumption High School in East St. Louis.

After college, Hudlin and his brother formed a production company and made music videos for artists like Heavy D, Jamaica Boys, and others. They were responsible for making the classic "Hey Love" 1980s-era TV commercial that played regularly on late night TV.

While an undergraduate at Harvard University, Hudlin directed his thesis project, a short film called House Party, which went on to receive numerous awards including first place at the Black American Cinema Society Awards. The film was inspired by his experience growing up in East St. Louis. In 1983, Hudlin graduated magna cum laude from Harvard with a B.A. in Visual and Environmental Studies. His short film thesis was the basis for his first feature film, House Party.

Hudlin directed, with older brother Warrington producing, his first feature-length film, 1990's low budget teen hip hop comedy House Party, which starred Kid 'n Play. One of the messages of the film was its promotion of safe sex. The film, which was made with New Line Cinema, according to Variety was one of the most profitable films of the decade. New Line wanted to make sequels, but the Hudlins did not feel the compensation or deals were adequate.

In 1992, while making Boomerang, Hudlin directed the first Black animated film, Bébé's Kids, which was championed by Paramount's Brandon Tartikoff and was made in memory of Comedian Robin Harris, who had died in 1990.

In 1994, the Hudlin Brothers produced the HBO anthology multi-ethnic horror series, Cosmic Slop, of which Hudlin directed the episode "Space Traders." "The Space Traders" was an adaptation of a Derrick Bell short story found in his book, Faces at the Bottom of the Well: The Permanence of Racism.

In 2002, Hudlin married Chrisette Hudlin (née Suter), a public relations consultant, in Montego Bay, Jamaica. They have two children.

During the time that he was President of BET, Hudlin wrote many of the Marvel Comics series Black Panther from 2005 to 2008, most notable for the 2006 storyline "Bride of the Panther," which saw the character marry X-Men leader Storm.

From 2013, Hudlin has executive produced the NAACP Image Awards. The show attained its highest rating on NBC in 2013, then became the highest rated show in the history of TV One in 2014. Hudlin produced a number of TV specials, including the 88th Academy Awards, hosted by Chris Rock.

In 2014, Hudlin produced the Black Movie Soundtrack celebration of Black music in movies, held at Los Angeles' Hollywood Bowl, and hosted by Craig Robinson. Black Movie Soundtrack II, also hosted by Robinson, was held in 2016.

In 2015, it was announced that Hudlin and artists Denys Cowan and Derek Dingle would be part of the relaunch of comic book company founded by Dwayne McDuffie, Denys Cowan, and Derek Dingle, Milestone Media.

In October 2017, Hudlin's film, Marshall, about Thurgood Marshall, the first African-American Supreme Court justice, starring Chadwick Boseman, was released. The screenplay is by Michael Koskoff and Jacob Koskoff and co-stars Josh Gad. The film was made in Buffalo, New York.