Koepka's birdie on the Jeddah Invitational's third play-off hole cost Uihlein an eye-watering $5.875m (£5.3m) as it denied him the winner's prize plus $8m (£7.16m) for second place in the season standings.
Uihlein can console himself with $4m (£3.5m) for third place this season, plus $2.125m (£1.9) for second place on Sunday and $750,000 (£670k) for winning the team event alongside Koepka.
Koepka can also add $750,000 (£670k) to his winnings for the team victory. The 2017-2018 US Open and 2018-2019 PGA Championship winner was emotional afterwards, revealing he had feared for his career while battling injury.
"The last two years haven't been fun - it's been a long road," Koepka said.
"I didn't know if my career was over for half-a-second. I wasn't sure if I was going to play so it's nice to be able to come back and be able to win."
The $25m (£22.4m) tournament in King Abdullah Economic City, north of Jeddah, was the first LIV stop in Saudi Arabia and the last individual event of a debut season that has split the golf world.
Koepka, who wrecked his knee in 2021 and has also had hip problems, said he would honour his pledge to buy his brother and team-mate, Chase, a lime-green sports car for winning the team title.
"I told my brother I'd buy him a Lambo (Lamborghini) if we won the team thing, so now, I've got to go buy one," he said.
Koepka's winnings far outstrip his prizes for any of his major titles. He took home $2.16 million from the US Open in 2017 and 2018, and $1.98 million from each of his PGA Championship victories.
Four-way tie
Uihlein began the day one shot ahead of Koepka and from the shotgun start, the former Challenge Tour room-mates duelled their way around the course on a hot day of stiff breezes and scant birdies.
Arriving at the 18th, their final hole, they were in a four-way tie for the lead but they both birdied to head into the play-off and leave Sergio Garcia and Joaquin Niemann behind.
Uihlein escaped from a greenside bunker twice to take it to a third hole but then, from an awkward lie in the sand, he wedged over the green and into the water to leave Koepka with two putts for the win.
Uihlein, 33, had stood to win $12.75m (£11.4m), nearly tripling his PGA Tour career earnings, if he had seen out the victory.
LIV's arrival as a deep-pocketed rival to the US PGA Tour and Europe's DP World Tour has divided golf, its players and its fans, with many calling it a "sportswash" of Saudi's human rights record.
This week's tournament, the first on Saudi soil, has also coincided with a political row between Washington and Riyadh over cuts in oil production by the Saudi-led OPEC+ grouping.
Tiny crowds at the Royal Greens course in King Abdullah Economic City, a remote development north of Jeddah, have not helped LIV live up to its "golf, but louder" slogan this week.
LIV tournaments, which offer lucrative prizes but no world rankings points, are played over 54 holes with no cut and a limited, 48-man field.
LIV, backed by Saudi Arabia's PIF sovereign wealth fund, concludes its debut season with a team event later this month at Trump National in Miami, with an expanded 14-stop circuit planned for next year.
