Hunter Haas, Ben Bates, Bryan DeCorso and Chris Nallen were at 4-under 68, with David Miller and Vance Veazey another shot further back at 3-under 69.
There were 66 players overall within five shots of Mulroy's lead, including 15 who were tied at 2-under 70 and 19 who were at 1-under 71.
Mulroy, a five-year pro from South Africa, had six birdies and one bogey Thursday at Kinderlou Forest, including four during a six-hole stretch from No. 2.
After making the turn at 4 under, Mulroy picked up birdies at the 11th and 12th holes, then dropped a shot with his only bogey of the round at the 16th.
But what most people don't talk about are a player's pars, and Mulroy saved an important one Thursday.
Staring at 12 feet for par at his first hole -- and desperately not wanting to open with a bogey -- Mulroy calmly rolled in the mid-range putt, then went on to make a spectacular birdie on No. 3 when his approach landed within tap-in range.
'Making that putt (at No. 1) gave me a lot of confidence. Then the birdie on the third hole really got me going,' Mulroy said.
Mulroy's only other first-round lead on the Nationwide Tour came at last year's Panama Championship, where he finished tied for 18th place. It marked the winless South African's only other overnight lead.
He credited a change in clubs with his success Thursday.
'I put in new clubs (this year) and they haven't felt good,' Mulroy confessed. 'I've been messing around with different sets of irons the last month or two and I haven't been playing very well. Last week I switched back to the irons I used last year and I'm starting to hit it a little better now.'
John Kimbell, who won the first South Georgia Classic last season as a 38-year-old rookie, stumbled to a 4-over 76 to fall nine shots off the lead.
No player has ever successfully defended a title on the Nationwide Tour.