DeJoria entered the world of hair care as an employee of Redken Laboratories. He was fired from this position, he claims over a disagreement on business strategies. In 1980, he formed John Paul Mitchell Systems with hairdresser Paul Mitchell and a loan for $700.
DeJoria co-founded the Patrón Spirits Company in 1989, is a founding partner of the House of Blues nightclub chain, and has interests in Madagascar Oil Ltd., Pyrat Rum, Smokey Mountain Bison Farm, llc, Ultimat Vodka, Solar Utility, Sun King Solar, Touchstone Natural Gas, Three Star Energy, Diamond Audio, a Harley-Davidson dealership, a diamond company (DeJoria), mobile technology developer ROK AMERICAS, the John Paul Pet company, which does hair and personal grooming for animals, and J&D Acquisitions LLC, the parent company for the Larson, Striper, Triumph, Marquis and Carver boat companies formed with Minneapolis-based investor Irwin L. Jacobs.
DeJoria has been active in the film industry as an executive producer and actor. He made a cameo appearance as himself, in the 2008 comedy You Don’t Mess with the Zohan, and also in The Big Tease as the fictional John Paul Mitchell. DeJoria also made a cameo appearance in the Showtime series Weeds season 2. He narrated and appeared in television commercials for Patron in November 2011. In 2012, using a video, DeJoria showed his support for Captain Paul Watson of the Sea Shepherd Conservation Society, when Watson was detained in Germany for interfering with shark finning operations.
DeJoria appeared on the November 1, 2013, broadcast of the ABC reality series Shark Tank as a guest investor, replacing series regular Robert Herjavec. He’s also been interviewed many times on podcasts and video series, including the Handshakin Video Series