Murray, now ranked No. 243 in the world, returned to singles action in August after undergoing career-saving hip surgery in January. He was looking to win his first ATP singles title since lifting the trophy at the Dubai Championship in March 2017, and his grit shone through as he came back from a break down in the second set to take the match to a decider.
The Brit would go on to win a back-and-forth final set 3-6, 6-4, 6-4.
"It means a lot," an emotional Murray said afterward. "The last few years have been extremely difficult, both me and Stan have had a lot of injury problems in the last couple of years. It's amazing being back in a final playing against him like that. It was a great match. Stan was playing unbelievable.
"I didn't expect to be in this position at all, and I'm very, very happy."
The former world No. 1's trademark resilience was quickly called into action as Murray was forced to save two break points in the second game, with Wawrinka converting his third to race to a 2-0 lead.
Murray had his own break points in the following game, but again his Swiss opponent was able to extend his lead.
At 3-0 down, Murray held serve to love to finally get on the scoreboard, but the deficit built up by Wawrinka proved insurmountable and the world No. 18 ultimately sealed the opening set with an unreturnable serve.
As with the first set, Wawrinka broke early in the second, taking a 2-1 lead after finding the line with a sharp backhand winner. He then wasted two break points in Murray's next service game, allowing the Scot to claw his way back to deuce before Wawrinka sent successive shots long past the baseline.
Wawrinka would come to rue his missed opportunity in the very next game, with Murray breaking back. The two-time Wimbledon champion failed to convert his first two break points, but fought his way back into the match with Wawrinka sending a backhand into the net after a lengthy rally -- sparking a trademark Murray roar.
Murray continued to dig deep, saving three break points in the ninth game of the set, leaving Wawrinka to serve to stay in it.
Not even an argument with the umpire at 30-30 could stop Murray from breaking Wawrinka's serve to take the set, with the Swiss sending a backhand into the net.
The drama continued in the final set with four breaks of serve in a row leaving the decider tied up at three games apiece.
The pair both held in their next service games as the tension in Antwerp mounted, but Murray clinched the match-clinching break -- taking the win on his first championship point.
"I think the tennis world, including me, was really sad in Australia after that press conference," Wawrinka said, referring to Murray's announcement at the Australian Open that he planned to retire after Wimbledon because of his ailing hip.
"To see you back at this level, it's amazing. We're all really happy. I'm sad I lost today but I'm really happy to see you back. You're an amazing champion and you deserve that. I've lost today, but in general, it was a great week."
The Scot underwent hip surgery after his first-round Australian Open exit. He returned to the tour to play doubles, winning the title at Queens in his first tournament back before partnering with Serena Williams at Wimbledon. He then made his singles comeback in August at the Winston-Salem Open.