Campbell, who closed with a one-under 70 at Vidanta Vallarta on Sunday (Monday AEDT), won for the first time since turning pro a decade ago.
Victory sends him to the Masters, The Players Championship and the PGA Championship, along with five of the $US20 million signature events left on the PGA Tour schedule.
"To be in this position is just so unreal - I can't believe it, really," 31-year-old Campbell said after calmly holing a birdie putt just inside four feet on the 18th green for the win.
Good golf wasn't enough. Campbell needed the break of a lifetime.
Campbell and Potgieter, who shot 71, each made birdie on the 18th in regulation and began the playoff with a par.
Returning to the par-5 closing hole for the third time - a big advantage for the power-hitting 20-year-old South African - Campbell hit a low, hard fade towards the out-of-bounds stakes.
But it crashed into the trees and popped back out into the rough. He still was 94 yards behind Potgieter, but at least he had a shot.
Campbell hit fairway metal to 68 yards short, then a lob wedge that checked up just short of the hole.
"You've got to get those breaks sometimes," Campbell said.
"Unfortunately I hit a really bad tee shot there, caught the tree, was able to keep it in play and get ourselves in a good position to get a wedge and keep the pressure on.''
Potgieter twice hit the 18th fairway in the playoff and had a six-iron for his second shot, and both times made par.
The first time was a hard draw over the green. On the second playoff hole, his shot looked on line but came up a foot short and into a bunker.
He blasted out some six feet by and missed the birdie putt, setting up Campbell for a moment that once seemed so far away.
Campbell was winless in 186 starts on the Korn Ferry and PGA Tour combined, earning $US1,487,830. His payoff on Sunday was $US1,260,000.
Potgieter started the final round with a one-shot lead, fell behind with two bogeys to end the front nine, then caught Campbell with a superb up-and-down on the par-5 14th. They each made one bogey coming in and finished at 20-under 264.
"Hopefully, my time will come soon," said Potgieter, who won the 2022 British Amateur at age 17 and last year became the youngest to win on the Korn Ferry Tour.
Isaiah Salinda finished with a bogey-free 65 to finish alone in third. American world No.29 Aaron Rai briefly shared the lead after an eagle on the par-5 sixth. He was one over the rest of the way for a 67 and tied for fourth with Ben Griffin (67).
Victory handed Campbell a two-year exemption through 2027 and gives him a busy March and April, with the Arnold Palmer Invitational, The Players Championship, the Masters and the RBC Heritage all on his schedule.
Aaron Baddeley was the leading Australian, tied for 34th at nine under after rounds of 67, 69, 68 and 71.
Compatriot Karl Vilips finished at even par for the tournament, tied for 72nd place after rounds of 74, 65, 76 and 69.
