With a four-under-par 67, the Northern Irishman is now tied for second place with Collin Morikawa and Alex Noren.
McIlroy reached four under par over the front nine thanks to an eagle, three birdies, and a bogey, but he was unable to build on that with three more birdies and three bogeys on the back nine.
Three times, McIlroy has emerged victorious at Quail Hollow, the site of his maiden PGA Tour victory in 2010.
“I feel like Charlotte has adopted me as one of their own, playing in front of these crowds.
It’s been an amazing adventure. I’ve made some very great memories, and I definitely want to start creating new ones.”
The seven-time PGA Tour winner Schauffele made six birdies and an eagle in his opening round, dropping just one stroke.
Tommy Fleetwood of England is tied for third place with Justin Rose and Matt Fitzpatrick.
