Early finisher Scott posted a five-under-par 66 at Liberty National for an 11-under-par total of 273 that stood up as Tiger Woods (69), US Open champion Justin Rose (68), Canadian Graham DeLaet (65) and Gary Woodland (73) all finished one stroke back.
It was Scott's first victory since his rousing playoff win over Argentina's Angel Cabrera at Augusta, and a frustrating loss for his pursuers, particularly Woods.
Woods, who complained of a sore back this week after sleeping on a soft hotel bed, collapsed to his knees after striking his second shot on the par-five 13th hole and grabbed at his back.
The shot sailed left and into a pond beyond the tee box at an adjacent hole. Woods went on to bogey that hole and the 15th as well before bouncing back with birdies at 16 and 17. He left his last birdie try two revolutions short of the cup.
Rose needed two putts from 30 feet at the last to tie Scott, but sent his 30-foot birdie try five feet past and missed the par putt.
Woodland had 10-foot birdie attempts at both 17 and 18 to join Scott on 11-under but missed both."I hit a good putt," the long-hitting American said about his chance on the 72nd hole. "Hit it right where I wanted to. Just went the other direction. Frustrating."
Tied for sixth place at nine under par were British Open champion Phil Mickelson, who fired a final-round 65, and fellow-Americans Jim Furyk (69) and D.A. Points (67).
While he had not won since the Masters, Scott continued to play very good golf. He tied for third at the British Open and tied for fifth at the PGA Championship earlier this month before claiming his 10th career PGA Tour victory on Sunday.
"It's been a great year for me," he said. "I've been playing consistently well and trying hard to get another victory this year and surprised myself with this one today.
"Got to keep it going now, three big weeks in the playoffs left and hopefully I can cap it off with a big win in the FedExCup," said the Australian, with an eye toward the $10 million bonus paid to the series winner.
"This win's for the new member of my family, Olivia, who was born yesterday," Scott said. "So big shout out to my sister and her husband. I'm thinking of you guys."
The top 100 on the FedExCup points list advanced to next week's playoffs event, the Deutsche Bank Championship in Boston.