A closing round of 71 was no match for Koepka, who carded a faultless 65.
Rory McIlroy's pursuit of majors and big titles is so often blighted by two things - his putter turning cold and him carding one poor round out of four.
On Sunday at the St Jude Classic, in Memphis, McIlroy's putting was off and, as a consequence, he could not compile a score to kick on from his overnight position as leader by one.
McIlroy has a solid conversion rate of taking Sunday leads all the way home to the winners' enclosure. On Sunday, he stayed ahead of Koepka, a fellow four-time major winner, for two holes, Koepka birdied the third then added two more on five and six and there was no looking back.
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For McIlroy, who went 79, 63 to narrowly miss The Open cut last week, it was a run of 11 straight pars as he struggled to drop the same putts he had been sinking over the previous three rounds.
When the Northern Irishman bogeyed the 12th, he had fallen four behind Koepka. The American had some wobbles down the stretch but his recovery game was spot on and he did not drop a single shot. Instead, the birdie on 17 sealed his victory and with it a winners' cheque of $1.75 million and a bonus of $2m for finishing top of the WGC 'Wyndham Rewards' rankings for 2019. $3.75m and the first man since Tiger Woods to win a major and the WGC in a calendar year.
McIlroy ended up finishing in a tie for fourth, on -11, as he was overtaken by Webb Simpson and Mark Leishmann. He remains third in the world ranking while Koepka, who showed up 45 minutes before his tee time and only hit nine practice shots, consolidated his position as World No.1. John Rahm climbs to 7th while Simpson's second saw him leap-frog Open winner Shane Lowry to No.17.
"It's incredible," Koepka said after his win. "I've always loved this place so to play so well here is incredible... to finally get the win here is special."
"I know [taking on McIlroy] was what everybody wanted and I think it would have been incredible if we had've both gone down 18 close, and someone would have had a putt to win it... Rory didn't play the way he wanted to today but it is still so much fun to watch him play... it is always nice to squeak out a victory over probably the best player right now."
On his lightning-quick practice, Koepka said, "I always take less time on Sundays. I mean, I'm already loose so I don't even need to hit balls. I've already stretched and I've already done everything. I don't know why everyone else is in a panic. I'm not!"
