Hopkins stopped De La Hoya with a pair of perfectly placed punches in the ninth round on Saturday night to retain his undisputed middleweight titles in perhaps the richest non-heavyweight fight.
The fight ended at 1:38 of the ninth with De La Hoya writhing in pain on the canvas, his goal of beating the fearsome middleweight champion crushed with shocking suddenness.
"I tried to do the impossible on paper - beat the middleweight champ coming up from 130 pounds," said De La Hoya.
It was the first time De La Hoya had been stopped in his career, and it came in a fight where he was competitive up until the two left hooks landed just below his rib cage near his corner.
While Hopkins celebrated, De La Hoya remained on his knees, his face buried in his gloves. He repeatedly pounded the canvas in frustration, his unlikely dream ending early.
"I felt a sense of urgency," said Hopkins. "I wasn't sure if I was winning or not."
De La Hoya made at least $30 million for the fight, but his place in boxing history was also on the line. He said the fight would define his brilliant career, and it just might have.
De La Hoya lost for the second time in three fights, and at the age of 31 found out he couldn't slug with middleweights after starting his career 12 years ago at 130 pounds and winning titles in five other weight classes.
Hopkins (45-2-1, 32 knockouts) was ahead on two scorecards and behind on a third when bout ended.
Hopkins fought cautiously in the first half of the fight, giving both De La Hoya and the sell-out crowd at the MGM Grand arena some cause for optimism. De La Hoya, who many thought would box and move, was the aggressor in many of the early exchanges.
"He came to fight," said Hopkins. "He didn't come to run or look for a gift from the judges."
De La Hoya was holding his own until the fight came to a stunning climax that quieted the shocked crowd as De La Hoya stayed on the canvas.
"He caught me right on the button," said De La Hoya. "Believe me, I tried getting up but I couldn't. I have what it takes, but he hit me right on the button."
De La Hoya was quicker inside and landed almost as many punches as Hopkins. But though the ringside stats credited him with 82 punches to 99 for Hopkins, he never landed any punches that seemed to bother the champion.