Weekley fired a 6-under 66 on Saturday and stands at 22-under-par 194 through three rounds -- besting the 54-hole tournament record by four shots.
Brandt Snedeker, who held at least a share of the lead after the first two rounds, shot a 3-under 69 and is alone in second place at 20-under-par 196.
Garrett Willis is in third place at 19-under-par 197 after a third-round 69, while Tim O'Neal (64) and Andrew Buckle (68) share fourth place, one stroke further back at Black Creek Club.
Weekley began the third round tied for second place, one shot behind Snedeker.
'I was a little nervous at first today because I ain't been in this position in such a long time,' he said. 'It's all new to me again.'
Weekley opened with four straight pars, then carded back-to-back birdies at the fifth and sixth. After a par at seven, Weekley collected consecutive birdies again at eight and nine to make the turn at 20 under.
Weekley's bogey-free week continued on the back nine with seven pars and birdies at the 15th and par-5 18th, as he claimed his first career 54-hole lead.
'I'm getting my feet wet again and getting back in it,' Weekley said. 'To be able to come out here and feel good about what I'm doing and have that confidence, it's started to show.'
Snedeker birdied two holes on the front nine, but was just 1 under on the back -- despite an eagle three at the par-5 18th.
A round of 3 under par just isn't good enough to maintain the lead in a tournament where the average score had remained in the 60s throughout.
'I hit the ball pretty good but made a couple of bad swings at the wrong times,' said Snedeker, a Vanderbilt graduate. 'I was a little tentative and I just couldn't get the speed down on the greens.'
Brad Adamonis shot a 6-under 66 and shares sixth place with Charlie Wi (67), John Merrick (68) and Rick Price (68) at 17-under-par 199. Johnson Wagner (65), Chris Baryla (66) and Scott Ford (66) are knotted one shot further back in 10th.