The 33-year-old Mitchell, winless on the PGA Tour since 2019, delivered a bogey-free round at Philadelphia Cricket Club, highlighted by nine birdies - including four in his final five holes.
"Everything kind of has to go your way to do that," Mitchell said. "I'm blessed that it did. I played great and hopefully I've got three more rounds to keep it going."
This year's event was moved from Quail Hollow in Charlotte, North Carolina, which is preparing to host next week's 107th PGA Championship.
Denny McCarthy sits one shot back after a 62, while fellow Americans Rickie Fowler, Akshay Bhatia, and Collin Morikawa - a two-time major winner - joined Austria's Sepp Straka at 63.
"I'm pretty proud of how I played, just stayed true to playing solid golf out there," Morikawa said.
Defending champion Rory McIlroy opened with a 66 to share 25th. Playing his first solo event since completing the career Grand Slam at the Masters, McIlroy carded six birdies and two bogeys, including a 15-foot make at the 10th and a closing birdie at the 17th.
"This was always going to be a great prep week for me to see where my game was and sort of refine a few things," McIlroy said.
"I still want to play well and I still want to have a chance to win the tournament, but I'll have a really much better gauge of where my game is going into next week after these four days than I would've had if I hadn't had played or if I just spent the week at home practicing. So it's an important week for me.
"Overall a decent day," he added. "I played pretty good. I felt like I was a little rusty out there, just hadn't played in a week and hadn't really done a ton of practice."