Straka seized the lead with a par on the 16th hole and shot a two-under 68 to clinch victory in the $US20 million signature event by two shots at Philadelphia Cricket Club's Wissahickon course on Sunday.
Irishman Lowry missed the green with his tee shot at the 212-yard, par-3 16th, chipped out of the heavy rough but failed to convert a 6-foot par putt, falling a shot behind.
Lowry then missed a potential tying 22-footer for birdie at the lengthy par-4 17th and, after driving into trouble at the 514-yard, par-4 closing hole, he finished with a three-putt bogey.
A tense back-nine duel between the two had an anticlimactic ending as Straka made a no-pressure, two-putt par to win at 16 under and joined Rory McIlroy (three victories) as a multiple winner on tour this season.
Straka also won The American Express in January and now has four career PGA Tour wins, also moving to No. 2 in the FedEx standings.
It's huge, the biggest win of my career," said Straka, who is poised to move into the top 10 in the world ranking and all but certain to make his second European Ryder Cup team.
"It's not the best ball-striking week I've had. Off the tee the first two days, I hit it terrible."
The difference, he said, was putting. He made more than 110 feet of putts in the final round.
Lowry posted a 70 and tied for second with Justin Thomas (67), two shots clear of Patrick Cantlay (65), Tommy Fleetwood (65) and Jacob Bridgman (65) .
Adam Scott led the Australian pack as he closed with a 68 and was tied 34th at four under, ahead of Min Woo Lee (70, tied 51st) and Cam Davis (72, tied 54th).
The Truist was another miss for Lowry, whose last PGA Tour victory was the 2019 British Open. He won the European tour's BMW PGA Championship in 2022.
McIlroy, the defending champion and four-time event winner at Quail Hollow, its usual venue, never really got going and closed with a 68.
Playing in his first individual tournament since completing the career grand slam at the Masters, McIlroy shot 68 and was in a group in seventh place at 10 under.
McIlroy now heads to his beloved Quail Hollow in Charlotte, North Carolina, for the PGA Championship, the year's second major.
"I think I'm in a good place," he said. "A couple little improvements and little tweaks, especially going to a place I love like Quail Hollow, and I feel like I'm in a really good spot."
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