Mickelson strolled off the 18th green to the roar of the crowd after dropping in a 12-foot putt that virtually clinched his first British Open championship and fifth overall major victory.
He finished at 3-under-par 281, three better than Henrik Stenson (1-under 70).
"Today's round will be one of the most memorable rounds of golf I've ever played," Mickelson said.
Lee Westwood, who led after three rounds, was derailed by five bogeys Sunday en route to a 4-over 75 and a third-place finish for the tournament, sharing the third spot with Masters champion Adam Scott (72) and Ian Poulter (67).
Mickelson's 66 was the low round of the tournament and included a highlight reel of crowd-pleasing shots.
"I putted amazing today and hit it as well as I ever have," he said.
Mickelson, who won the Scottish Open last weekend, closed with birdies on four of his final six holes. He reached the 18th green in two with a fairway wood on the par-five 17th, then two-putted from 35 feet for birdie.
The front nine had shaped up as a three-way battle between Westwood, Scott and Stenson before Mickelson began his late surge with a birdie on No. 13.
Scott opened the door for him by stumbling to four straight bogeys from No. 13.