The 25-year-old triumphed by one shot in a three-hole showdown after the pair ended tied at eight under in Atlanta. Bradley earlier triple-bogeyed the 15th to hand Dufner a five-shot lead but kept his nerve as his rival faltered.
Luke Donald and Lee Westwood both halved their three-shot deficits during Sunday's absorbing final round but stumbled late on to end three under.
But the world's top two-ranked players were no more than bit players as the unheralded pair of Dufner and Bradley ignited the tournament with some late fireworks.
Bradley, who won his maiden PGA Tour event earlier this year, becomes the first American to clinch a major title since Phil Mickelson won the Masters in 2010. He is also the seventh consecutive first-time major winner and the 13th different winner in the past 13 majors.
And he joins 2003 Open winner Ben Curtis in being the only players since Francis Ouimet at the 1913 US Open to have triumphed on their first appearances at a major.
"I can't believe it, I feel so proud," said Bradley, who is the nephew of LPGA legend Pat Bradley.
Ranked 108th in the world, Bradley went into the final day one shot behind joint overnight leader Dufner and fought back from a shaky start to join his compatriot at the top of the leaderboard on nine under after an eagle on the 12th.
But his challenge seemed to be over after chipping through the green into the water on 15, before back-to-back birdies on 16 and 17 kept him in the hunt.
The 34-year-old Dufner, still chasing a first PGA Tour win, had stretched clear with four birdies in 13 holes, but his tee shot into the water on 15 sparked his demise. He bogeyed the 15th, 16th and 17th to drop back alongside Bradley, with Denmark's Anders Hansen finishing one shot back after a 66.
In the play-off, Bradley birdied the first hole, the 16th, to Dufner's par and then made par on the short 17th as his rival dropped a shot. Dufner birdied the 18th but Bradley's par was enough to hand him the Wanamaker Trophy.
Dufner said: "Those are tough holes, but it was disappointing. There's a lot to be learnt from this."
World number one Donald was four under for his round through 12 holes but caught the water off the 15th tee to effectively scupper his chances. Another bogey on the 18th sealed the 33-year-old's fate as the leaders stretched clear.
"It was a missed opportunity again," said Donald, who carded 68 to end tied eighth with Westwood. "At the beginning of the day I thought if I could get to six or seven under I might have a chance.
"At four under through 12 and still being three back I thought I had to press a bit and take on some pins.
"I took a tighter line than I normally would on 15 but I just hit a poor shot. I didn't strike it well enough."
Did you know?
• Bradley is only the third player ever to win a major title at his first attempt
• The others were Ben Curtis at the 2003 Open and Francis Ouimet at the 1913 US OPen
The 38-year-old Westwood will also have to wait until next year for the chance to break his major duck.
The Englishman had also crept to four under for the day with birdies at the eighth, 10th and 12th, but was unable to make further inroads and found the water on the 18th to end with a bogey for a 68.
"I played lovely again. It's just one of those things," said Westwood, who has had five top-three finishes in his last nine majors.
"I have enjoyed playing great for a long time now, but unfortunately when I turn up to majors and I don't win it's a disappointing week for everybody it seems - and obviously for me."
American David Toms, who won the USPGA at the Atlanta Athletic Club 10 years ago, shot 67 to end tied fourth on five under with countryman Scott Verplank (70) and Sweden's Robert Karlsson (67).
Australian Adam Scott, who won last week's WGC event, was another stroke back after a 68, while US Open champion Rory McIlroy took 74 to end 11 over.
International Federation of PGA Tours | US PGA Championship 2011 | Atlanta Athletic Club
ROUND 4 Clubhouse Scores | Par = 70
Monday, 15 August 2011
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