Chris Riley reached 6 under on his round with a birdie at the 17th but he bogeyed the last to finish one shot back at 5-under-par 66. Riley finished in a tie for third with Vijay Singh.
Byrd, who earned his first career victory on the PGA Tour last year at the Buick Challenge, got things started with a birdie at the par-5 second at the TPC at Deere Run.
He found trouble with a bogey at the very next hole but managed to recover with a remarkable stretch of golf.
Byrd hit a 7-iron to five feet for a birdie at the fourth and followed that up with a birdie at the fifth.
He then knocked his approach within a foot of the hole for a birdie at the sixth and made it four in a row after his tee shot to the par-3 seventh landed inside 12 feet.
'When you've got hole locations and you feel like you're hitting five or 7-irons, you feel like flying it all the way to the hole,' said Byrd. 'Being able to do that makes things a lot easier.'
The 25-year-old continued his fine play on the inward nine with a two-putt birdie at the par-5 10th and climbed to minus-6 with a birdie at the 17th.
'My attitude has been great the last month and that's all I've been trying to work on and hoping the game would follow with it, and I'm starting to hit it better,' said Byrd, whose last top-10 came at The Masters. 'It's been a struggle lately, but I'm just trying to stay patient.'
Lewis, whose lone PGA Tour victory came at this event in 1999, played the back nine first and jumped out of the gate with a birdie at the 10th. He then added a birdie at the 17th to reach 2 under around the turn.
'I think it's kind of marked my career,' Lewis said of his victory. 'That was definitely one of the best, if not the best, so I have a lot of good memories here.'
The 43-year-old caught fire on the front side with 15-footer for birdie at the first. Lewis then made it two in a row at the par-5 second when his third shot stopped 12 feet from the hole.
Lewis tallied a birdie at the sixth and dropped a lob-wedge inside eight feet for a birdie at the eighth en route to a bogey-free round.
'I love this golf course,' said Lewis. 'It's a great layout. When the wind is up, you have to hit it low and work it, so this golf course adds some dimensions that other golf courses don't.'
Singh had a strong finish with an eagle at the 17th and a birdie at the last to finish one shot off the lead.
'Well, you've got three days to go,' said Singh. 'You've got to be focused on what you're doing tomorrow. I'm just going to go out there and focus on what I'm doing and play a hole at a time and see what happens.'
Garrett Willis, Tom Scherrer, Chris Smith, Notah Begay III, Billy Mayfair, Skip Kendall, Bob Burns and Dennis Paulson tied for fifth place at 4-under-par 67.
Joey Sindelar, Mark Wilson, Tommy Armour III, Aaron Barber, Esteban Toledo and Jeff Maggert were one shot further back at 3-under-par 68.
PGA Tour money leader Davis Love III scattered three birdies and a double bogey to finish at 1-under-par 70 in a group that featured defending champion J.P. Hayes.
The first round was suspended due to darkness with one player, Scott Laycock, left on the course.