Tucker began showcasing his comedy skills before an audience in local Atlanta comedy clubs until he decided to move to Los Angeles in 1990 to further pursue his stand-up comedy career. In 1992, Tucker was a frequent performer on the HBO comedy series Def Comedy Jam.He made his cinematic debut in House Party 3 in 1994 and gained greater film recognition alongside N.W.A rapper Ice Cube in Friday the following year. In 1997, he co-starred in the films The Fifth Element and Money Talks. He also played a supporting role in Quentin Tarantino's Jackie Brown and had a starring role in the spy comedy Double-O-Soul, but was never released.
Along with Hong Kong martial artist Jackie Chan, Tucker starred as LAPD detective James Carter in the martial arts action comedy film series Rush Hour. After the commercial success of the first Rush Hour film, he held out for a $20 million salary for Rush Hour 2, and was paid $25 million for Rush Hour 3. The latter was part of a $40 million two-movie contract with New Line Cinema that also included an unnamed future film. He was also to receive 20% of the gross from Rush Hour 3.
Tucker did not reprise his role as Smokey in Next Friday (2000) or Friday After Next (2002) for religious reasons, later explaining that he didn't want to encourage others to smoke weed. He starred in Michael Jackson's video "You Rock My World" and made a cameo appearance in Tupac Shakur's "California Love".On February 13, 2009, Tucker participated in the NBA All-Star Weekend's Celebrity Game. Other celebrities participating included rapper Master P, NBA Hall of Famers Clyde Drexler and Dominique Wilkins, wide receiver Terrell Owens, and four Harlem Globetrotters.
Tucker was announced in 2007 to star in the New Line drama film Mr. S: My Life with Frank Sinatra, directed by Brett Ratner and based on George Jacobs's autobiography of working as Frank Sinatra's valet during the Rat Pack era of 1953–68.
In 2011, Tucker made a comeback to stand-up comedy. The next year, he returned to film in Silver Linings Playbook, co-starring Bradley Cooper, Jennifer Lawrence, and Robert De Niro. Tucker's performance in the film was well received by critics and audiences alike. The film itself received numerous nominations and awards including the Broadcast Film Critics Association Award for Best Cast. He also hosted the 2013 BET Awards. In 2016, he appeared in Billy Lynn's Long Halftime Walk.