Third-ranked Schauffele sank a tension-packed six-foot birdie putt on the par-5 18th hole at Valhalla for a one-stroke victory over DeChambeau to snap a two-year victory drought.
"I was actually kind of emotional after the putt lipped in," said Schauffele. "It has been a while since I've won.
"I kept saying it all week. I just need to stay in my lane. And man, was it hard to stay in my lane today. But I tried all day to just keep focus on what I'm trying to do."
Schauffele, who had 12 prior top-10 major finishes without a victory, had not won an event since the 2022 Scottish Open, having had 19 top-10 PGA Tour finishes during his drought.
But he matched the lowest round in major history with a nine-under 62 on Thursday and was equal to the challenge on Sunday.
The reigning Olympic champion fired a six-under par 65 and finished 72 holes on 21-under 263 to edge fellow American DeChambeau, the 2020 US Open champion.
Schauffele broke the old 72-hole record low under-par winning score of 20-under, done four times, most recently by Australian Cameron Smith at the 2022 British Open.
Victory was worth $3.33 million to Schauffele from an $18.5 million purse while DeChambeau took home $1.998 million.
"Proud of Xander for finally getting the job done," DeChambeau said. He's an amazing golfer and well deserved major champion now.
"On my side of the coin, disappointing. I played well. Shot 20-under par in a major championship. Proud of myself for the way I handled adversity. Definitely disappointing, but one that gives me a lot of momentum for the rest of the majors."
DeChambeau closed with a 64 while Norway's Victor Hovland, last year's PGA runner-up, was third on 266 after shooting a 66.
Belgium's Thomas Detry fired a 66 to share fourth on 269 with Collin Morikawa, the 54-hole co-leader who made 16 pars in shooting 71. England's Justin Rose and Ireland's Shane Lowry shared sixth on 270.
DeChambeau rolled in a birdie putt from just beyond 10 feet at the par-5 18th hole, the ball barely dropping in, to match Schauffele for the lead at 20-under.
Seconds later, Hovland missed his 10-foot birdie putt to doom his chances and ended up making a bogey.
Schauffele's tee shot at 18 was in the left rough on the edge of a fairway bunker. He calmly blasted his second shot 36 yards from the hole in the fairway short of the green and dropped his approach six feet from the hole.
The ball made a slight roll on the edge as it fell in to give him a wire-to-wire triumph, counting shared leads.
Not since 2005 Phil Mickelson at Baltusrol had a player birdied the 72nd hole to win the Wanamaker Trophy.
"I just told myself this is my opportunity and just capture it," Schauffele said.
He put past defeats in perspective with a text from his father -- a steady drip breaks the rock.
"That's actually what my dad texted me," Schauffele said. In German though. I had to ask him what the translation was."
Hovland, last year's FedEx Cup playoff champion and PGA runner-up, was denied his first major title.
DeChambeau, the top finisher among 16 LIV Golf entrants, led the field in driving distance.
Scheffler shares 8th
World number one Scottie Scheffler fired a 65 to finish on 271 and share eighth with fellow Americans Justin Thomas and Billy Horschel.
He had his first over-par round of the year on Saturday, a day after being arrested and jailed after a traffic incident at the entrance to Valhalla.
"I'm proud of how I fought," he said. "Kind of running on fumes."
Four-time major winner Rory McIlroy of Northern Ireland shot 67 to finish on 272. Second-ranked McIlroy has not won a major since 2014 at Valhalla but has since had 20 top-10 major finishes.
American Jordan Spieth, trying to win to complete a career Grand Slam, fired a 73 to finish on 278.
