It was the 34th career victory for Mickelson, who began the final round with a one-stroke lead. But like he did the day before, Mickelson fell behind before regaining the lead on his final putt of the day.
Mickelson had a closing 2-under 68 to finish at 14-under 266. Mickelson won at Colonial in 2000, and has won 11 tournaments multiple times.
After saving par out of a greenside bunker at 188-yard 16th, Pampling still led by a stroke.
But on the ensuing drive at the 382-yard 17th, Pampling (68) hit the ball way right toward a ditch. He had to take a penalty stroke after a drop'though that put his ball where it could be seen rather than buried in heavy rough at the edge of a concrete gully. He managed to get the approach shot into a bunker, then blasted to 4 feet, pushing both arms in the air before tapping in the bogey. That came after Mickelson had two-putted from 28 feet for par.
Mickelson still kept it interesting, pushing his final drive well left into the rough between trees. Pampling put his drive in the center of the fairway.
Lefty calmly hit the shot, then took a couple of steps before jogging out of the trees to see the ball fall near the flag. Pampling left his approach 38 feet away, making his par after Mickelson made the winning putt.
Pampling may have still done enough to get into the top 50 for a spot in the U.S. Open.
Clark had birdies at Nos. 16 and 17 to get to 13 under'and tied for the lead'that same stretch where Pampling first saved his lead only to blew it after his next shot.
Pampling hit his tee shot at 16 into the right greenside bunker, and blasted within 9 feet. After Mickelson made par, Pampling took extra time to examine his line and then saved par, and his one-stroke lead, pumping his right fist hard in the air as the ball dropped into the hole.
As Mickleson and Pampling were finishing No. 17, Clarks 14-foot birdie chance at the closing hole curled just short and he finished with a round of 66.
Stephen Ames (70) finished fourth at 269, a stroke ahead of Ben Crane (67).
Mickelson earned $1.098 million, nearly double the $594,000 check he got for winning the last Colonial eight years ago, and surpassed $49 million in career earnings. He is the 11th player to win multiple times at Hogans Alley, where five-time champion Ben Hogan is the only golfer to win more than twice.
Mickelson was back within a stroke after getting on the green at the 611-yard 11th in two, then two-putting from 33 feet. Pampling, the Australian native who lives in nearby Flower Mound and gets to play Colonial often, hit his first two shots at the hole out of the rough before a 13-foot birdie chance stopped right by the hole.
But they kept matching pars after that'until the final two holes.
When Mickelson got to the 6th tee in front of the huge scoreboard Sunday, he still had a one-stroke lead over Pampling. That was the spot the day before when Mickelson realized he had dropped out of the lead and three strokes behind Pampling, who was in a different group then.
But Mickelson didnt hold his lead much longer.
After driving into the right rough at the 394-yard hole, Mickelsons shot from there hit a tree branch and ricocheted left into the fairway, though he managed to save par after hitting the third shot within 3 1/2 feet. But Pampling got even with a 48-foot birdie putt off the fringe, after coming out of his stance once and turning around to ask a spectator to turn off their phone.
Then at No. 7, Pampling outdrove Mickelson by 60 yards and made a 7-foot birdie putt to get to 13 under, a stroke ahead.
Pampling made it a two-stroke lead after his approach at No. 9 was within 4 feet for another birdie. Mickelsons 16-foot attempt slid right of the hole.
Ames began the day tied with Pampling for second place, but came up short on some early chances and couldnt stay out of the bunkers.
Clark, who hasnt won yet on the PGA TOUR, got to 11 under with birdies at Nos. 6 and 8, the latter a par-3 where he made a 20-foot putt. But Clark had only pars until his consecutive birdies late.
Mickelson is the seventh Colonial winner who had at least a share of the 54-hole lead. Geoff Ogilvy, the No. 7-ranked player, followed an opening 72 with three subpar rounds and finished tied for seventh at 273. Oglivy and Mickelson were the only of the five top-10 players in the field to make the cut.