Mathis started birdie, hole-in-one, birdie and rode that wave to a round of six-under-par 64 on the TPC River Highlands layout.
In search of his first US PGA Tour victory, Mathis leads a group of three players, Sweden's defending champion Fredrik Jacobson, Australian Nathan Green and American Will Claxton, on 65.
The first round featured scorching temperatures near 100 degrees and a hot grouping of major champions with US Open victor Webb Simpson playing alongside fellow Americans Bubba Watson and Keegan Bradley.
Masters champion Watson, a winner here in 2010, started his round with consecutive birdies and the back nine with an eagle on the par four 10th after holing out from 137 yards.
He finished at four-under 66 along with Simpson, who got to five under with a birdie at 15 but slipped back with a bogey at the next.
"It was fun playing with those guys and we just fed off each other and played a good solid round," Simpson said.
Bradley, winner of the 2011 US PGA Championship, finished at two under.
Mathis followed up his ace with a birdie at the 12th then had consecutive birdies on 14 and 15. He carded two more birdies on his back nine, including one on the 9th, to close out his round.
"I played really solid all day and was hitting a lot of great shots," Mathis said. "To make a hole-in-one and then the long birdie on 12, it really got me jump started for the day."
Jacobson got off to a strong start with back-to-back birdies at the 3rd and 4th. In all, he had six birdies over his first 12 holes including three straight starting at the par three eighth.
Coming off a tie for 15th at the US Open, Jacobson got to seven under with a birdie at the par four 14th but slipped out of the lead with a costly double-bogey at the par three 16th where his tee shot rolled off the back of the green.
A birdie putt at 18 just slid by to keep Jacobson in a tie for second, but he was far from disappointed with his round.
"I have some good memories here and today my goal was just to go out and get off to a decent start," Jacobson said. "I had a few close calls but did make some putts along the way too. I thought we had that one on 18 but it was still a good day."