In a surprising display of power, the 33-year-old De La Hoya (38-4, 30 KO), known as boxing's Golden Boy, knocked Mayorga down three times.
Referee Jay Nady stopped the bout 1:25 into the sixth round after De La Hoya punished the near defenseless Mayorga (28-6-1) into the ropes by using a stiff right cross and left hook combination.
"You are a great champion" Mayorga, who had made several disparaging pre-fight remarks, said to De La Hoya after the bout. "You are a great fighter. I apologize for everything I said to you."
De La Hoya had not fought since Sept. 18, 2004, when he was knocked out by Bernard Hopkins in the ninth round of a fight for the undisputed middle-weight title.