Three times on the final day of the final major golf event of the year, Dufner hit an approach from the fairway to within a foot of the cup and those birdies led to a 2-under 68 at the Oak Hill Country Club.
His 72-hole total of 10-under 270 was good enough for a two-shot victory over third-round leader Jim Furyk, who was trying to win his second major crown 10 years after winning his first at the U.S. Open.
Henrik Stenson, who finished second at the British Open last month and second a week ago at the Bridgestone Invitational, wound up in third place, three shots behind.
Dufner had a five-shot lead late in the final round of the PGA Championship two years ago in Atlanta only to wind up losing to Keegan Bradley in a four-hole playoff.
He began Sunday's round a shot behind Furyk, moved to two shots in front through nine holes and kept that lead the rest of the way.
Dufner bogeyed the two closing holes, the two hardest tests on the course, but Furyk did the same and thus was unable to put pressure on the front runner.
After a sensational 2012 season, Dufner has been out of the spotlight for much of this year. Over the last month, however, he has had strong finishes at two major championships and a World Golf Championship event and that play continued this week at Oak Hill.
He equaled he lowest round ever shot in a major event on Friday, firing a 7-under 63, and narrowly missed producing a 62 that would have put him alone in the history book. The 63 was the 26th ever shot in a major championship and he became just the sixth player to turn in such a score en route to a title.
Dufner joined Adam Scott (Masters), Justin Rose (U.S. Open) and Phil Mickelson (British Open) as this year's major championship winners. Of the 20 winners of major championships over the past five years, 15 have achieved the feat for the first time.
Dufner saved par after a poor tee shot at the second, then showed that Sunday might be his day when he put his second shot at the dangerous, par-4 fifth to within 12 inches of the hole. He did the same thing at the par-4 eighth and again at the 16th.
Jonas Blixt was alone in fourth at 274 while Scott Piercy and Adam Scott tied for fifth at 275.
Tiger Woods completed another year without a major title, his last one having come in 2008. Woods shot a 70 Sunday for a 284 total that left him in a tie for 40th place. Of the 75 players who made the cut, Mickelson finished in front of just two of them with a 292 total.
There were 102 sub-par rounds shot during the week at Oak Hill, none of them turned in by Woods or Mickelson.