It was the first fight in the welterweight division for De la Hoya, who also holds the WBC super-welterweight title and has previously won the International Boxing Federation's junior-lightweight and lightweight belts.
"I thought it was a close fight but I believe I did more than enough to win," said De la Hoya, who took his record to 24 wins and no defeats and furthered his claim as the world's best pound-for-pound boxer. Whitaker, who was making the ninth defence of his WBC title, fell to his first defeat in more than nine years.
"I told you all along that his southpaw style was going to give me problems and it did," De la Hoya said. "He's by far the hardest I've ever faced."
Indeed, De la Hoya suffered the fight's only knock-down, in the ninth round, when Whitaker caught him with a left hook on the side of the neck, putting him on one knee.
"Oscar is a good fighter but there's no way I lost this fight," Whitaker said. "It was a blow-out, a shut-out. I should have gotten 10 of the 12 rounds." The 33-year-old had not been defeated since losing a controversial decision to Jose Ramirez in Paris in March, 1988 - which he easily avenged 18 months later.
Whitaker landed 232 of 258 of his punches, while de la Hoya managed only 191 of 557. "I'll give him a rematch anytime, anywhere," De la Hoya said. "I'm frustrated because I can do better, much better."