Spending nearly as much time in hospital as on the PGA Tour, the injury-prone Texan turned a back nine rally and nervy 18th at the Muirfield Village Golf Club into a 16-under 272 for his second career title.
Three-times Memorial champion Tiger Woods, playing his first event since his record run of 142 consecutive PGA Tour cuts ended at the Byron Nelson Championship three weeks ago, rebounded with a solid performance to bolster his U.S. Open preparations.
Woods carded a final round 68 to finish in a tie for third with Bo Van Pelt and Jeff Sluman at 12-under 276.
Even par through the front nine, Bryant mounted a determined charge at the turn with four birdies, but sealed the victory with a gritty 15-foot par putt on the last after his tee shot had found a hazard to leave Couples needing a birdie to tie.
Along with the $990,000 purse, the victory carried a special bonus for the 42-year-old journeyman, earning him a spot in the U.S. Open at Pinehurst in two weeks time.
"I was going home early tomorrow morning and I was going to drive to Tampa tomorrow night and play the U.S. Open qualifier," Bryant said. "I guess I can change my flight now."
The success also vindicated the determination Bryant has shown just to remain on the Tour.
"You know, there were times when I'd lay in my bed at night and think, 'you know, what am I doing? I need to get a job and provide for my family a little better than what I'm doing right now,'" he added.
"There's always been a seed of doubt in my mind that this would never happen. Luckily, I have just a lot of strong people around me that kept lifting
It was the second win in nine months for Bryant, who collected his maiden title at the Texas Open last September, rewarding his resilience in a career disrupted by two elbow and shoulder operations that has limited him to only six full seasons since 1991.
COUPLES SURGE
"I'm almost speechless, it's a real honour to win here at Jack's (Nicklaus) tournament," said Bryant, who has made six successful trips to Qualifying school during his career.
"At the beginning of day I had high hopes but there are so many good players out there.
"I knew someone was going to shoot 67 or 68 to win it, I just didn't know it was going to be me."
While Bryant's story is compelling, it was another underdog, Fred Couples who had the massive galleries cheering.
Without a win since 2003, Couples's chances of returning to the winner's circle appeared slim going one over through his first eight holes.
However, the former Masters champion carded five birdies on his next seven holes to surge to the top of the leaderboard, much to the approval of the galleries.
But the hard work was undone by a bogey on 16, and a second Memorial title slipped through his fingers despite a three-under 69.
"Bart deserved to win," Couples said. "It was nip and tuck with four or five people, then we pulled ahead and I had a great time.
"I can't really kick myself too hard. You know, there are a lot of shots out there and there are a lot of things that I did to save shots too, but overall I just needed one more putt.
"Bart has been through a lot and he's a great, great player. What a great victory. I can relate to winning here and it'll be one he'll never forget."