Fleetwood carded a closing 67 to finish 17 under par, a shot ahead of US Open champion Dustin Johnson – who eagled the last – and Spain’s Pablo Larrazabal.
Three-time winner Martin Kaymer also eagled the 18th to finish in a tie for fourth with Thailand’s Kiradech Aphibarnrat and Austria’s Bernd Wiesberger on 15 under.
The victory lifts Fleetwood from 102nd to just outside the top 50 in the world, with the top 50 on March 27 earning an invite to the first major of the year at Augusta National.
The 26-year-old from Southport was a lowly 188th in the rankings at the start of September, but has reaped the rewards of returning to his former coach Alan Thompson and employing his friend Ian Finnis as his caddie.
“I thought maybe my second win would come sooner to be honest,” said Fleetwood, who won the Johnnie Walker Championship in 2013.
“I had a really hard time from July 2015 to July last year where I really struggled with my game. It’s been an awkward curve and massive comeback.
“The only thing left was getting a win, but I kept thinking, ‘you keep knocking on the door, it will come’. I didn’t really think it would be this week. I’ve made the cut here once in five years so it just shows that makes no sense at all.”
Fleetwood began the day a shot off the lead and got off to a poor start with a bogey on the third, but then birdied the eighth, chipped in for an eagle on the 10th and birdied the 11th.
That took him into a share of the lead with playing partner Aphibarnrat, who did superbly to salvage a bogey on the 12th after finding water off the tee before bouncing back with a birdie on the next.
A birdie on the 16th saw Fleetwood regain the lead and – after a wild drive on the last hit a spectator – he effectively made sure of the win with a brilliant three wood onto the green to set up a two-putt birdie.
“On 18 I got a good break,” Fleetwood admitted. “It took me a few drops (from a cart path) to get the perfect spot but I just had a go at it. You’ve got to take those chances if you want to win. To be honest, that (approach) was easier than the four foot putt to win in the end.”
Aphibarnrat missed birdie attempts on the 16th and 17th, leaving Johnson and Larrazabal to jump into second place with an eagle and birdie on the 18th.