Fleetwood got plenty of help at the start when Patrick Cantlay began Sunday's final round in Atlanta bogey, double-bogey and could never catch up.
Scottie Scheffler hit his opening tee shot out of bounds and still was a threat until a tee shot into the water ended his hopes on the 15th.
Through it all, Fleetwood held his nerve. He closed with a two-under 68 for a three-shot victory over Cantlay (71) and Russell Henley (69).
"I've been a PGA Tour winner for a long time, it's just always been in my mind," Fleetwood said. "A lot of close calls, but I've always enjoyed the challenge."
His first PGA Tour victory came with two trophies - the FedEx Cup and the "Calamity Jane" replica putter for the Tour Championship.
Ryder Cup captain Keegan Bradley was within one shot of the lead on the front nine, but wound up with a 70 to tie for seventh. He said he was "dead tired" and now has to decide whether to use one of his six captain's picks on himself.
But this day, this moment, belonged to Fleetwood, enormously popular around the world for coping with so many close calls with a refreshing perspective and joy for those who beat him.
An eight-time winner around the world, no stranger to big stages at the Ryder Cup or his silver medal at the Olympics last summer, Fleetwood was constantly reminded about his failure to win on golf's strongest circuit.
He saw a one-shot lead turn into a one-shot loss at the Travelers when he took three putts from the front of the green and Bradley made birdie.
Fleetwood let a two-shot lead with three holes left get away from him at the FedEx St Jude Championship to start the post-season.
For all the hurt, he never lost hope.
Thousands of fans surrounded the 18th green at East Lake on Sunday to watch the 34-year-old from England, all of them chanting, "Tommy! Tommy! Tommy!"
Justin Rose, who rallied past him to win two weeks ago, and Shane Lowry stuck around to share in his big moment.
Fleetwood removed his cap when he tapped in for par, looked to the cloudy sky and let those long locks flow as he let out a yell.
"This wasn't the most comfortable I've been," Fleetwood said with a smile. "I feel like I've had a great attitude throughout it all. ... I'm so happy I got it done."
He started the final round tied for the lead with Cantlay, the 2021 FedEx Cup champion searching for his first win in three years. Cantlay made bogey on the first, three-putted for double-bogey on the second and suddenly was four behind.
Cantlay never went away, and a two-shot swing on the 10th - Fleetwood made bogey from the left rough, Cantlay made a five-foot birdie - narrowed the gap to one shot. The next three holes were pivotal.
Cantlay failed to get on the green from a bunker on the par-3 11th and made bogey. Fleetwood birdied the next two holes, and Cantlay could only match one of them.
The last big hurdle was the 218-yard 15th to a peninsula green, where Fleetwood went in the water on Saturday and made double-bogey. This time he managed a bogey and didn't miss a step the rest of the way in finishing at 18-under 262.
American Cameron Young shot 66 to tie for fourth with Scheffler and Corey Conners (62), strengthening his bid to make his first Ryder Cup team before home fans in New York.
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