Heavy afternoon rain made conditions tricky, with course workers scrambling to keep the course dry between groups to keep play going.
The tournament was relocated from its usual venue at Quail Hollow in Charlotte, North Carolina, as that course is set to host next week's 107th PGA Championship.
Mitchell, chasing his first PGA Tour victory since 2019, carded a three-under 67 to reach 12-under 128 through 36 holes at Philadelphia Cricket Club.
The 33-year-old American opened the tournament with a career-best 61 on Thursday. His only PGA Tour win came at the 2019 Honda Classic, though he recently finished runner-up at Puntacana.
"A lot more up and downs. The greens were tougher to hit because we had a lot more club, a little bit more wind and the rain," Mitchell said. "It definitely played tougher. Didn't hit as many greens but I thought my short game was pretty good. I've got to keep my head down and keep moving."
Ireland's Lowry, the 2019 Open champion, shot a five-under 65 to move within one stroke of Mitchell. Austrian Sepp Straka sits third at 10-under 130, while defending champion McIlroy and recent RBC Heritage winner Thomas are part of a group tied for fourth at 133 after a pair of 67s.
"It was pretty good," Lowry said. "Weather has turned a bit nasty but I thought early on it was actually OK, it was like not the worst, wasn't that much wind. I'm very happy but it's pretty miserable out there for the rest of the guys.
"There's a consistency to my whole game that has been very good. I think I'm just maturing as a golfer, taking the rough with the smooth, the good days taking them well and the bad days working through them."
McIlroy carded six birdies and three bogeys in his round, twice bouncing back with birdies immediately after dropping shots, to finish the day five shots back in a tie for fourth. He shares the spot with Thomas, South Korea's Kim Si-woo, Akshay Bhatia, Collin Morikawa, and Patrick Cantlay.
The Northern Irishman is playing his first solo event since winning the Masters to complete the career Grand Slam. This week also serves as his final tuneup before the PGA Championship at Quail Hollow, a course where he's claimed four victories.
"I've putted nicely, which has been good to see," McIlroy said. "I've seen my lines pretty well the first two days.
"My focus is good. I made some uncharacteristic mistakes over the first to days compared to the way I've played the most part of this year. If I can just iron those out... it would be nice to go out there and not have to scramble so much. If I can clean the cards up over the weekend I'll be in a good spot headed into Quail Hollow."