Okerlund got his start at Am talk station KOIL-AM 1280 in Omaha Nebraska as a DJ. In the 1970s he segued out of radio into a position at the American Wrestling Association (AWA) in the early 1970s when he occasionally filled in for ailing ring announcer and interviewer Marty O'Neill, eventually becoming O'Neill's permanent replacement by the end of the decade. He would stay with the AWA until 1984, when he was one of many AWA personnel to join the expanding WWF. He would stay with the WWF for nine years, as he was their top interviewer, and was host of such WWF shows as All American Wrestling. In 1993, he left the WWF, and would become an interviewer for World Championship Wrestling (WCW). He would stay with WCW until it was sold in 2001 to the WWF.

Okerlund would then re-join the WWF (renamed WWE in 2002), as his first post-WCW assignment for the company was as a commentator for the Gimmick Battle Royal during WrestleMania X-Seven along with Bobby Heenan. He would go on to host WWE Confidential in 2002, and was there during its entire two-year run. In 2004, he received a kidney transplant, and recovered fully from the operation. As of 2005, he still makes occasional appearances for WWE.

Okerlund is perhaps most famed for interviewing Hulk Hogan and Ric Flair. During the interview, Hogan would get all fired up and say, "Well you know something, 'Mean' Gene!" and Flair would often say "Meeeean, Gene" or "'Mean,' by God, Gene!". The Iron Sheik referred to Okerlund as "Gene Mean."

On February 27, 2006, WWE announced Okerlund as the third member of the WWE Hall of Fame Class of 2006. Hulk Hogan inducted Mean Gene on April 1, 2006 in Chicago, the night before Wrestlemania 22. It was at that night where he requested to, when he died, be buried face first, so all his critics can "kiss my ass."