The American entered the final day a shot off the lead and after an opening birdie he made ten pars in a row as the world class field around him at Chapultepec Golf Club jostled for position.
Bryson DeChambeau and reigning Race to Dubai Champion Jon Rahm both made big moves up the leaderboard but a hat-trick of birdies from the 15th saw Reed power past them both and open up a two shot lead.
There threatened to be late drama when the 2018 Masters Tournament Champion sprayed his tee shot a long way right on the last, but Reed kept his composure and a closing bogey saw him finish a shot ahead of countryman DeChambeau at 18 under.
Reed's win is his third on the European Tour and his second at this event after his triumph in Florida six years ago.
The victory rockets him to the top of the Race to Dubai Rankings Presented by Rolex and will also take him back into the top ten on the Official World Golf Ranking.
"It's very rewarding," he said. "My team and I, we've worked so hard through the end of last year and also at the beginning of this year and kept on feeling like we were playing some good golf, just we weren't quite able to get over that hump.
"To come back and win my second World Golf Championship, especially with how I had to finish from basically 15 onwards - the last hole was ugly but it was what I needed just to get the job done.
"I think the biggest thing is every time I feel like I go to the golf course, anytime I go out and work with my coach, anytime I'm at home, I always feel like I have something to prove.
"Not to anyone else but to myself, that I can continue to improve on and off the golf course and continue to do the unthinkable and pull off hard shots, make putts when I need to make them, just do the little things.
"And I think because of that, it just has built up so much confidence with how I've played so far in my career with putting myself in these positions, I feel like I have a chance to continue and to have a chance to win these golf tournaments. The confidence is through the roof."
Rahm carried the momentum from Saturday's stunning 61 into round four, getting up and down on the first and second and putting a tee shot to four feet on the third.
Reed birdied the first despite finding the greenside bunker and he would then make those ten pars in a row as those around him battled for supremacy.
Rahm birdied the fifth from 13 feet to get into a four way tie for the lead but it was then playing partner DeChambeau's turn to produce some fireworks.
After missing good chances on the first and second, he put his tee shot to five feet at the third, made the most of the par five sixth and chipped in at the seventh to get to 14 under. He dropped a shot on the next but hit stunning approaches into the ninth and tenth to join the lead.
I feel like I have a chance to continue and to have a chance to win these golf tournaments. The confidence is through the roof
An up-and-down at the par five 11th put him ahead on his own and when he put an approach to nine feet at the 12th, he led by two.
Reed trimmed the lead with an approach to tap-in range at the 12th but DeChambeau restored his cushion with a shot to 14 feet from a nasty lie on the 14th.
An up-and-down from just off the green at the par five 15th brought Reed another birdie and when DeChambeau three putted the 17th from a long way out, the lead was shared.
Reed was not in the best position off the tee at the 16th but his second was exquisite as he used the contours of the green to leave himself three feet and took the lead.
A 17 foot birdie putt on the 17th brought a fist pumping celebration and a two shot lead that gave the Reed the luxury of being able to bogey the last.
Rahm's challenge faded as he came home in level par with birdies on the 13th and 15th but bogeys on the 11th and 14th.
Van Rooyen took his score on the first and second this week to ten under with a birdie-birdie start but dropped a shot on the next before a double bogey on the tenth fatally stalled his momentum.
The 30-year-old - who celebrated his birthday on Friday - followed a birdie on the 11th with a bogey on the 12th before gains on the 15th and 16th got him back into red numbers for the day.
Northern Irishman McIlroy birdied the first, fourth and sixth to turn in 32 and get into contention but came home in level par with a bogey on the 12th and a birdie on the 16th.
Tyrrell Hatton was making his belated first appearance of the season after a wrist problem and finished at 13 under alongside Hideki Matsuyama and Justin Thomas, one clear of Billy Horschel and Kevin Na.