Two off the pace heading into the final round at Firestone Country Club, Lowry overhauled third-round leaders Jim Furyk and Justin Rose, and held off a charging Bubba Watson with a closing four-under-par 66 in overcast conditions.
The bearded Irishman, ranked 48th in the world, registered four birdies and several clutch par saves in a flawless display on a tree-lined layout where danger lurked at every corner to post an 11-under total of 269.
American left-hander Watson, ranked third and bidding for his third PGA Tour victory this season, also signed off with a 66 to secure second place in an elite field of 77 players at the World Golf Championships event.
Lowry's final birdie of the day came at the par-four last where he struck his second shot from the left rough through trees and over a bunker to 11 feet beyond the flag, then coolly sank the putt.
"I played as good a golf as I've ever played the last four days," Lowry, 28, a double winner on the European Tour, told CBS Sports after celebrating his birdie on the 18th green with three fist pumps.
"I managed to hole a few putts and get a bit of luck. I was quite nervous with a few holes to go. But I made a lot of good decisions, hit the ball well. It's such a good feeling to shoot a bogey-free 66 on the golf course like that."
Lowry became the first player from Ireland to win a WGC title and earned a three-year exemption on the PGA Tour through the 2017-2018 season.
English world number eight Rose and sixth-ranked American Furyk were not at their best on Sunday and carded matching 72s as they slipped back into a tie for third at seven-under.
They both covered the front nine in one-over to trail Lowry by one shot before the Irishman, after hitting a wayward drive at the 10th, conjured a miracle second shot from rough left of the 11th tee, his ball settling two feet from the flag.
That set up a tap-in birdie for a two-shot lead.
Lowry, who became only the third amateur to win a European Tour title with his victory at the 2009 Irish Open, did well to save par at the 14th and 17th with clutch putts before sealing victory with his unlikely birdie at the 18th.
Masters and U.S. Open champion Jordan Spieth, who had been a distant nine strokes off the pace overnight, signed off with a sparkling 66 to surge into a tie for 10th at four-under.
(Editing by Larry Fine)
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