Marquez was losing by one point on all three scorecards when he landed his big punch.
It will go down among the great fights of their era. But it was barely over when the cry arose for the two ever-so-willing warriors to do it again.
The two fought to a draw eight years ago at 125 pounds, and Pacquiao was awarded close decisions in two other fights.
"If you give us a chance, we'll fight again," Pacquiao said. "I was just starting to feel confident, and then I got careless."
Indeed, the case could be made that Pacquiao was on the verge of a big win himself when Marquez landed the punch that sent him falling face first on the canvas. He had come back from a third-round knockdown to drop Marquez in the fifth and was landing big left hands that broke and bloodied the Mexican's nose.
Both fighters had vowed to be more aggressive in their fourth meeting. Pacquiao ended up paying the price for it when he tried to close the sixth round with a flurry, a big mistake against a counterpuncher who drew him into his sights.
"I knew Manny could knock me out at any time," Marquez said. "I threw the perfect punch."
Pacquiao hadn't been stopped in a fight since 1999 in Thailand when he was a 112-pounder.
He was taken to the hospital for a precautionary brain scan, then went to his hotel to watch a TV replay.
Pacquiao had dropped Marquez four times in their first three fights, but Marquez had never put him down before he landed a big right hand in the third round for his first knockdown. The power was sure to raise questions about the new, bulked-up physique Marquez has at the age of 39, which he said came from hard work under a strength coach who once provided steroids to track star Marion Jones.
Pacquiao lost a controversial decision in his last fight to Timothy Bradley and many in boxing believe he is showing the wear of 17 years in the ring. But Pacquiao showed no sign that he was willing to quit and return to his other job as a Philippines congressman.
One thing the loss did do was scuttle, perhaps forever, what might have been the richest fight in history. Any fight against Floyd Mayweather Jr. would now be fought for a lot less money and generate less interest.