Spaun tapped in to birdie the par-5 16th and holed a 17-foot birdie putt at the 17th then stood alone at the top after Austrian Sepp Straka missed a nine-foot par putt at the 18th at TPC Southwind in Memphis, Tennessee.
The 31-year-old American stood on 13-under 197 through 54 holes with Straka on 198 after shooting 68.
British Open champion Cameron Smith of Australia fired 67 to share third on 199 with Americans Will Zalatoris and Trey Mullinax. Americans Tyler Duncan and Troy Merritt were another stroke adrift.
The tournament opens the FedEx Cup playoffs, three season-ending events with a winner’s prize of $18 million.
Only 125 players qualified on season points and only the top 70 advance to next week’s BMW Championship, where the 30 qualifiers for the Tour Championship in Atlanta are decided.
Spaun won his first PGA title after 147 tour starts in April at the Texas Open while Straka, who missed six consecutive cuts coming into this week, won his first PGA title in February at the Honda Classic.
Spaun began with nine pars before a bogey at 10, but sank an 11-foot birdie putt at the par-3 11th and overtook Straka with his closing surge.
After a birdie-bogey start, Straka sank a 15-foot birdie putt at the fifth hole and another from just inside 12 feet at the sixth to seize the outright lead, but he fell back with a bogey at seven.
Straka took the lead alone with a 16-foot birdie putt at the 13th and grabbed a two-stroke lead by sinking a six-foot birdie putt at 15, setting the stage for Spaun’s run.
Zalatoris in the hunt
Zalatoris, still chasing his first PGA Tour victory, was a runner-up this year at the PGA Championship and US Open and last year in his Masters debut.
“I played on the biggest stages in three majors and I felt comfortable in those positions,” he said. “I haven’t gotten a win out of it yet. Eventually we will and hopefully tomorrow is it.”
World number 14 Zalatoris, who turns 26 on Tuesday, has a PGA-high eight top-10 finishes without a victory this season.
“Today was awesome,” Zalatoris said of his 65. “Tee to green was great and I rolled in a couple nice putts, so I just need to keep that going.”
Zalatoris split with caddie Ryan Goble last week and new caddie Joel Stock has read his putts the past 36 holes.
“It has been great,” Zalatoris said. “He has been awesome. Obviously it has paid off. He’s doing a good job.”
Mullinax, who shot 66, won his first PGA title at last month’s Barbasol Championship. He began the week 70th in points, the last spot to advance, but is in position to leap into the top 30.
“Been playing really well,” he said. “Just going out and sticking to the game plan.”
Duncan birdied four of the first six holes to shoot 67. It has been 77 starts without a top-10 finish for Duncan since his lone PGA victory at the 2019 RSM Classic.
Rickie Fowler found water twice on the way to a quintuple-bogey nine on the 18th hole. He shot 72 to stand on 208, likely dooming his bid to advance in the playoffs.
Reigning FedEx Cup champion Patrick Cantlay shot 71 to stand on 206.
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