Fleetwood finished with a four-round total of 277 to edge Fox by one shot after the New Zealander bogeyed the last hole, with India’s Sharma a further shot back in third place.
However, the Englishman had been unsure if he could compete at the Sun City tournament, dubbed ‘Africa’s major’, which he won when it was last hosted in 2019, before the outbreak of the COVID-19 pandemic.
"It was touch and go on Thursday morning,” Fleetwood said. “Then Saturday when we were up early and I felt like I had nothing in me. I was really poorly again.
"The doctor here has been amazing. I just gave his little son the winning golf ball. Without him there was not a chance on Thursday I'd have played,” he added.
The second round started on Friday but had to be completed on Saturday after an intense Highveld storm saw the golfers taken off the course because of fears of lightning.
On Sunday, inclement weather saw play again halted for several hours, disturbing the rhythm of some players but not Fleetwood who came storming down the final nine to win by a stroke from New Zealander Ryan Fox.
"It was such a lovely feeling coming down the back nine with a chance," said Fleetwood, who also lifted the trophy in 2019. "You draw on the good memories that you have round somewhere you've won. I felt good all day."
Fleetwood holed an eagle from the bunker on the 14th to pull level with Fox and Sharma and set up an absorbing final four holes at the Sun City resort.
"It wasn't the best lie but I felt okay," said Fleetwood. "It wasn't a terrible place to be. I don't know how far it would have gone past but it came out lovely and went in. That spark, those kind of things, happen."
Sharma's challenge ended with bogeys at 16 and 17, and when Fleetwood tapped in for par at the last, after almost sinking a huge birdie attempt, Fox paid for a poor tee shot and posted his only bogey of the day at the worst possible moment.
It denied Fox a chance to go top of the tour rankings before the season-ending DP World Tour Championship in Dubai next week.
"I played great and didn't miss a shot until the 18th," Fox said. "I certainly would've like to have played the 18th a little bit better and made Tommy work a little bit harder, but it's an incredibly tough golf course to play down the stretch.
"All of us were there or thereabouts with three holes to play, but Tommy was the one who held it together. Fair play to him. If you had given me second at the start of the week, I definitely would've taken it," he added.
