The end came minutes after the fight-altering punch as Garcia (24-0, 15 knockouts) knocked down Khan (26-3, 18 KO's) two more times in the fourth. That forced referee Kenny Bayless to stop the fight at the 2-minute, 28-second mark even though Khan insisted he was OK.
"I rewatched some of the replays and saw that I was coming in with my hands a little low, and Danny took advantage of it. I respect Danny," said the 25-year-old Khan, a 7-to-1 favorite who might have moved into a marquee matchup with Floyd Mayweather Jr.
"He was countering well against me. I got complacent, and he took advantage and caught me."
Had Khan stuck to the plan that gave him the first two rounds - using speed and combinations that created a cut over Garcia's right eye - things might have been different.
Instead Khan - who is of Pakistani descent - seemed intent on proving Angel Garcia, his opponent's outspoken father and trainer, wrong in his prefight claim that "Pakistanis can't fight."
"I think Mr. Garcia got under his skin," said Freddie Roach, Khan's trainer. "He wanted to go out and knock this guy out. He threw combinations and pulled out and got caught on the end of a big shot. Garcia can punch, and that's how it goes."
When Khan and Garcia picked up the pace in the third round, the slugfest proved costly for Khan. He missed on a combination and Garcia connected with a vicious left hook that caught Khan at the base of the neck, dropping him to the canvas. He avoided getting counted out, but his legs were wobbly.
Garcia floored him twice more in the fourth before the bout was called.
"If Danny was walking down the street, he looks like you could take the money out of his pocket, like he was a little kid," Angel Garcia said. "He looks like a kid on his way to Sunday school. They underestimate him because of the way he looks, like a baby, a little kid."
Over the last 15 months, Danny Garcia defeated veterans Erik Morales, Kendall Holt, and Nate Campbell. But critics argued that his aging opponents were near the end of their careers.
"I hit him with the same punches I hit Morales with," said Garcia, who claimed the vacant WBC title with a 12-round decision over Morales in March.
"That goes to show you how great Morales was. People said he was old, but Morales took the punches all night long and Khan couldn't."
Garcia said he doesn't have any immediate opponents in mind, but the former Juniata Park resident said he would defend his belts as a true champion from Philadelphia would.
"I come from the streets of Philadelphia, where a lot of people don't make it out of there," Garcia said. "I bring that into my fights all the time. I say if I lose this fight, I will die in the ghetto, but for me to die in the ghetto, you have to kill me in the ring.
"I never fought on this level before, but I knew that I was built for this and I knew I was born to be in the limelight."