Reigning Olympic champion Schauffele, last year's Wells Fargo runner-up, closed with a bogey to finish on 11-under 131 after 36 holes at rain-soaked Quail Hollow in Charlotte, North Carolina.
"Just trying to plod around the property, knowing if you hit a drive somewhere near the fairway it's going to plug and stay in it," said Schauffele.
"Really kept each hole in front of me and it's only Friday. Just happy to be in this position."
World number two Rory McIlroy and Australia's Jason Day shared second on 135 with South Korean Im Sung-jae and American Taylor Moore on 136.
A lightning strike within 10 miles of the course halted play with 21 golfers still on the course, lowest among them being two-time major winner Collin Morikawa, in the 18th fairway on 6-under.
The PGA Tour signature event, with a reduced field and no cut, is the last major tuneup for next week's PGA Championship at Valhalla, where Schauffele hopes to win his first major title.
Schauffele seeks his eighth career PGA Tour triumph this week. The 30-year-old American has not won since the 2022 Scottish Open.
"I've had a few knocks on the door here and I just keep telling myself to keep knocking," Schauffele said.
"You're always going to think about (winning). The tough part is just to stay present, to recognize the situation you're in and realize you're playing some good golf and to get out of your own way sometimes."
Schauffele sank birdie putts from just outside seven feet at the fifth and eighth holes around a tap-in birdie at the par-5 seventh after reaching the green in two.
At 10, Schauffele dropped his approach inches from the hole and tapped in for birdie. He sank a birdie putt from just inside five feet at the par-3 13th to reach 12-under with a six-stroke edge.
But at 18, he hit his approach over the green, then chipped to 14 feet and lipped out on his par putt.
McIlroy fired a bogey-free 68 while Day made five birdies in a six-hole stretch on his way to a 67.
"Anytime you can go around this golf course bogey free it's always going to be a decent day," McIlroy said. "Set myself up for another good go at it this weekend."
McIlroy, a back-nine starter, sank a five-foot birdie putt at the 10th and pitched from greenside rough to within inches of the hole to set up another birdie at the par-5 15th.
At the eighth, McIlroy's approach landed two inches from the hole, setting up a tap-in birdie.
"It was solid," McIlroy said. "I probably could have squeezed a couple more shots out of it but overall really pleased with my game. It has felt really under control the last two days."
Day creeping back
Four-time major winner McIlroy is a three-time champion at Quail Hollow, with wins in 2010, 2015 and 2021.
"If I'm driving the ball well, I can take advantage of that at this course more than any other golf course on tour," McIlroy said.
"I can carry some of the doglegs, carry some of the fairway bunkers. That gives me a huge advantage into some of these par-4s," the 35-year-old Northern Ireland star said.
Day birdied all three par-5s on offer, two of them in his birdie run from the seventh through 12th holes.
Day hasn't had a top-10 finish since February.
"It has been a bit of a struggle but I'm starting to slowly creep my way out of it, which is nice," Day said. "The last two days is good to see."
