Owen began doing standup in 1995 while stationed with the Navy in San Diego, California. The following year he started driving to Los Angeles on weekends to perform standup in the city. According to Owen, his stand up was initially not well-received by audiences. In 1996 he was invited to perform at a comedy club in front of a majority black audience. Recalling the experience in 2015, Owen told Buzzfeed News that when he first performed for a majority black audience, "I was shocked when I walked onstage and told the exact same fucking joke and it worked. And that was when I knew."

After a year of doing stand-up, Owen was named "Funniest Serviceman in America". He continued doing stand-up in San Diego and developed a large African-American fan base. He went on to win the "Funniest Black Comedian in San Diego" contest. That led to his first gig at The Comedy Store in Hollywood. In July 1997, he auditioned for BET's Comic View. Two appearances on the multicultural comedy showcase won him his own one-hour Grandstand show. At the end of the season, he was selected from the year's four "Grandstanders" to be the host. Owen was the only white man to have ever hosted Comic View.

In April 2011, Ebony dubbed Owen "Black America's Favorite White Comic". Owen has produced two stand-up DVDs: Breakin' Out The Park, which is now available nationwide, and Urban Legend. He was also one of the headliners on Martin Lawrence Presents: 1st Amendment Stand-Up on Starz.

Owen starred in the Screen Gems comedy Think Like a Man — based on Steve Harvey's book Act Like a Lady, Think Like a Man — with Kevin Hart and Gabrielle Union.

Owen has also appeared in such films as Rebound, College, Daddy Day Care and Highway, and had a recurring role on Tyler Perry's TBS show House of Payne as Zack. He appeared in the comedy "Meet the Blacks" as Larry. He has a TV show on BET called The Gary Owen Show.

He has released the comedy specials Gary Owen: True Story (2012) and Gary Owen: I Agree with Myself (2015), and Gary Owen: I Got My Associate's (2017), all directed by Leslie Small, as well as Gary Owen: #DoinWhatIDo (2019), directed by Brian Volk-Weiss. In 2021, Owen released his comedy special Gary Owen: Black Famous on Showtime cable network that was also directed by Volk-Weiss.