Kris Cox shot a 7-under-par 65 and is alone in second place. Dan Olsen, Kyle Thompson, Jon Rusk and Jason Hill are knotted in third place at minus-6.
Barber began his round on the back nine at the Pete Dye Golf Club and birdied his first three holes, but dropped one at the par-3 13th. He then ran off three birdies in a row from the 15th to make the turn at 5-under-par 31.
Barber, who played with Annika Sorenstam when she teed it up at the Colonial two years ago, birdied the first hole to reach 6 under for the championship. He birdied the third and eighth holes to polish off his best round on the Nationwide Tour.
'Overall I'm very pleased with my round,' said Barber, who took his first solo first-round lead in his career. 'I was wedging it in there pretty good today. I drove it better today than I have in a long time. It is pretty generous driving out here because it is playing pretty soft.'
Barber has struggled of late, missing the cut at both the U.S. Open and Lake Erie Charity Classic.
'I got my butt kicked at Pinehurst,' said Barber, who is 55th on the Nationwide Tour's money list. 'But I am starting to get my confidence back. It is good getting some confidence under my belt again.'
Cox collected seven birdies and no bogeys in his 64.
Scott Weatherly, Troy Matteson, Steven Bowditch, Ryan Armour, Brian Kortan and Todd Demsey share seventh place at 5-under-par 67.
Kip Henley, winner of The Golf Channel's Big Break II, suffered a triple-bogey 6 on the par-3 fourth en route to a front nine 40. The Crossville, Tenn., native finished with a 4-over 76 and will need a strong second round in hopes of breaking through and making his first cut of the year.