In the biggest match-up of undefeated welterweights since Oscar de la Hoya and Felix Trinidad clashed in 1999, a big left hook from the champion pitched Hatton face first into the ring post and then on to his back in the corner.
The Manchester fighter hauled himself to his feet at the count of nine but Mayweather unleashed a combination of punches to send Hatton sprawling back toward the ropes.
Referee Joe Cortez moved in to stop the contest as Hatton collapsed on to his back again.
"He walked right into it and never saw it coming," Mayweather (39-0) told reporters of the left hook which sent Hatton to the canvas.
"I felt alright," Hatton said. "I felt really good and really strong. But I left myself open." Hatton (43-1) began strongly, rocking Mayweather with a left hook in the opening round.
He pressed forward relentlessly for the next several rounds, swarming the American and keeping him pinned against the ropes.
However, Mayweather maintained a tight defence which nullified Hatton's attacks.
"He's better inside than I expected, with all the elbows shoulders, and forearms he used," Hatton admitted.
A Mayweather punch opened a cut above Hatton's right eye at the end of round three, and the Briton said he felt the fight turn against him at that point.
"I felt alright until he got me with the cut," he said. "I didn't feel his punches until I was cut.".
Much of the fighting was tough and scrappy and Cortez warned both fighters to avoid roughhousing several times in the bout, and deducted a point from Hatton in the sixth for hitting Mayweather behind the head.
Mayweather began to take control of the fight in the fourth, using his jab to open the distance between the two men and give him more room to throw short, sharp counter punches as Hatton moved toward him.
By the seventh and eighth rounds, Mayweather was timing Hatton's assaults with regular counters and was landing frequent heavy jabs that snapped back the Englishman's head.
A straight right hand from Mayweather buckled Hatton's knees in the eighth, and in the ninth, the American connected with a sequence of punches that landed heavily on Hatton's jaw.
Still, however, Hatton continued to come forward until the fateful tenth.
Afterward, the champion paid tribute to the challenger "He was definitely the toughest competitor I ever faced,"he said.
Hatton vowed to rebound from the first loss of his career.
"I'll be back. Don't you worry," he said.