The Northern Irishman, who had endured a title drought since his play-off victory here over tournament host Tiger Woods in 2010, ended his 2012 campaign on a triumphant note as he closed with a four-under-par 68 to post a 17-under total of 271.
Though McDowell survived a few anxious moments over the closing stretch at a rain-soaked Sherwood Country Club, he rebounded from a bogey at the 13th with birdies at the 16th and the par-four last to keep Bradley at bay.
McDowell, who won his first major title in the 2010 US Open at Pebble Beach in Northern California, coolly sank a six-footer on the 18th green to claim the winner's cheque for $1 million with his fiancée Kristin Stape looking on.
"I'm just over the moon to kind of get the job done," McDowell told reporters after improving his remarkable World Challenge record to two wins and a runner-up spot in three starts.
"It’s been too long. Its been a hell of a two years since I sat here as a winner, and we all put winning kind of up on a pedestal as the ultimate goal.
"Keegan really pushed me today. He played great, and we really separated ourselves from the field and kind of made it the matchplay-type vibe."
Bradley finished second after signing off with a 69. American Bo Van Pelt (70) was alone in third at 10 under, a stroke better than compatriots Rickie Fowler (69), Jim Furyk (70) and five-times champion Woods 71.
"Overall I struggled with my game this week," said defending champion Woods, who had been bidding for a fourth victory this year. "I didn't quite have it.
"It's been a tough week for all of us. Just tough conditions to get the ball close. And yesterday and today it played really long."
Two ahead at the start of another rain-soaked day at Sherwood, McDowell maintained his advantage when he and playing partner Bradley both recorded two-putt birdies at the par-five second.
Bradley trimmed McDowell's lead to one when he rolled in a 15-footer to birdie the fifth but he bogeyed the par-three eighth, after missing the green off the tee, and the ninth, where he three-putted, to slide three shots back.
Both players birdied the par-four 10th before McDowell tightened his grip on the title by draining a curling 30-foot birdie putt at the 11th to stretch his lead to four.
However, Bradley benefited from a two-shot swing at the par-five 13th where McDowell recorded his first bogey in 42 holes.
While the American two-putted there for birdie, the Northern Irishman stumbled to a three-putt bogey after finding the right rough off the tee for his lead to be halved to two strokes.
Bradley never got closer though as McDowell saved par on 14 after finding rough off the tee, sank a 10-foot birdie putt at 16 and almost holed out for birdie from greenside rough at 17.
"It was a good battle today," said Bradley after mixing five birdies with two bogeys. "Graeme just played so great. He just had one three-putt. Other than that, he just played awesome.
"Graeme really likes this place. Just when I thought maybe I'd have a good chance, he'd hole a putt or hit a chip like he did on 17. He's a champion, so I don't expect anything less out of him."
World Challenge leaderboard after fourth and final round:
271 Graeme McDowell (Northern Ireland) 69 66 68 68
274 Keegan Bradley (US) 69 69 67 69
278 Bo Van Pelt 70 68 70 70
279 Jim Furyk 69 69 71 70
Rickie Fowler 73 67 70 69
Tiger Woods 70 69 69 71
281 Webb Simpson 70 73 69 69
282 Steve Stricker 73 71 68 70
283 Hunter Mahan 71 73 71 68
Bubba Watson 71 74 67 71
284 Matt Kuchar 73 69 72 70
Nick Watney 67 73 71 73
285 Brandt Snedeker 75 68 73 69
Dustin Johnson 74 68 72 71
287 Jason Dufner 73 68 75 71
Jason Day (Australia) 71 75 72 69
288 Ian Poulter (Britain) 73 72 71 72
293 Zach Johnson (US) 74 70 70 79