He credits his late brother Daniel and his other brother Dennis for getting him started as a trainer and supporting him throughout his career. Dennis recommended that the team purchase I'll Have Another at auction. He worked as an assistant to trainers Jude Feld, Hector Palma, Richard Mandella, and Doug Peterson before taking out his license in 1994. He won his first stakes race with Tanks Forthemusic in the 1996 CTBA Marian Stakes at Fairplex Park, and his first major stakes winner was Classy Cara, winner of the Fantasy Stakes and Honeymoon Handicap, and third in the 2000 Kentucky Oaks. He finally broke through with his first Grade 1 winner with Sky Jack in the 2002 Hollywood Gold Cup.
Other stakes winners from the O'Neill barn include Fleetstreet Dancer, Sharp Lisa, Cambiocorsa, Cobalt Blue, Notional, Enriched, Informed, Necessary Evil, Acting Lady, Super Freaky, Itty Bitty Pretty, Pohave, Hosco, Skipaslew, Avonzado, Estate Collection, Mistical Plan, Areyoutalkintome, and Supah Blitz
Unfortunately, Doug O'Neill's rise to the spotlight has also drawn attention to his numerous violations in the past. He is facing a 180-day suspension over failed tests for several of his horses for elevated levels of total carbon dioxide; the California Horse Racing Board said any suspension would start after the Belmont Stakes. He was suspended in 2010 for 15 days and fined $1000 for the same violation. In addition, one study found that his horses break down at a rate of 12 per 1000 starts, more than double the national average. In 2010 he claimed a 5-year-old mare named Burna Dette for $25,000, raced her at Del Mar where she was well beaten, then dropped her in for the fire-sale price of $2,000 at Los Alamitos two weeks later. Sadly she broke down and was euthanized on track in that race.