England's Fleetwood finished on 19-under-par overall after a birdie in the final hole earned him a 67 in the final round, with McIlroy and South Africa's Thriston Lawrence (27) one-shot behind in a thrilling finish at the Dubai Creek Resort.
"It was great. I think I was very happy with the way I played today for the large majority of the round," Fleetwood said.
McIlroy's birdie on the 17th put him on 19-under par overall to take the solo lead for the first time in the round, but he hit the water on the final hole and Fleetwood held his nerve and birdied to win his seventh DP World Tour title.
"First week back out, I think you have to expect some of those sloppy mistakes. Unfortunately for me, some of those mistakes came at the wrong time," McIlroy said.
Fleetwood began the day one-shot ahead of the world number two and was made to battle all the way by McIlroy and Lawrence, who produced a flawless seven-under-par 64.
McIlroy hit three consecutive birdies early on the back nine to draw level before being undone by a second bogey of the day on the 14th.
However, Fleetwood's only bogey of the round at the 16th set up the grandstand finish, with the Englishman finishing off with two birdies.
"I didn't hole some of the putts that I wanted to and it was great watching one of the world's best players in golf in Rory, watching the way he attacked the back nine," Fleetwood said.
"It was just up and down towards the end. Sloppy bogey on 16th. But birdie, birdie on 17 and 18."
