Poston fired a seven-under par 65 to overtake fellow American Ryan Gerard, finishing on nine-under 135 after 36 holes in the event, hosted by legend Jack Nicklaus at Muirfield Village in Dublin, Ohio.
"I was hitting my irons good and controlling them well and made a ton of putts, which was nice to see," Poston said.
"It helps to get off to a great start, making birdies early and seeing a few putts go in, makes it easier to be patient, feel like you don't have to press."
Poston, who turned 33 on Monday, seeks his fourth PGA title, his first since the 2024 Shriners Children's Open in Las Vegas.
Poston opened with a 22-foot birdie putt and followed with a 20-footer at the second hole, sank a three-foot birdie putt at the par-three fourth, and a 16-footer to birdie the par-five fifth.
After a bogey at the sixth, Poston answered with birdies from just inside 17 feet at the par-five seventh and 11 feet at the par-three eighth.
"When it's blowing out there, it's tricky," Poston said. "The targets are getting smaller and smaller where you've got to land the ball."
Poston seized a share of the lead with a seven-foot birdie putt at the 13th and took the solo lead on a 20-foot birdie putt at 17, then rescued par after finding bunkers on his first two shots at 18 by rolling in a 10-foot par putt to finish nine shots under the field average of 74.
"I'd like to keep staying patient, take it one shot at a time," said Poston. "I've done a good job of that this week. Made a lot of putts, hit irons well, would like to hit a few more fairways with driver."
Gerard, who shared the 18-hole lead, fired a 69 to stand on 136. He birdied three of the first six holes but had two birdies and two bogeys over the final six, a three-putt bogey at 18 keeping him from sharing the lead again.
"Overall, I'm proud of how I grinded from the spots I put myself in off the tee," Gerard said. "Made a lot of grimy kind of up-and-downs and really cool hack-outs, and I just felt like I did a good job of keeping myself in the hole.
"No matter where I was or what the position might be, I did a good job of just staying in the hole and grinding until the end."
American Sam Burns was third on 138, with England's Tommy Fleetwood fourth on 140 and American Eric Cole fifth on 141.
Reigning US Open champion JJ Spaun, gearing up for his US Open title defense at Shinnecock in two weeks, shot 77 to stand on 144.
World number two Rory McIlroy, the reigning Masters champion, had two bogeys and a double bogey in the last six holes to shoot 74 and stand on 145.
Top-ranked Scottie Scheffler, trying to become the first player to three-peat at a PGA event since Steve Stricker won the John Deere Classic from 2009-2011, fired a 72 to stand on 145.
"I was not hitting it very well," Scheffler said. "Overall, it was a tough day. I felt like I could have shot 90."
