The Irishman fired seven birdies and had just one bogey blemish as he produced an excellent back nine to move ahead of English duo Ross Fisher and Lee Westwood, on five and four under respectively.
Spain's Miguel Angel Jimenez was three under, with last year's winner Robert Allenby a shot back after shooting a one under 70, the same score as England's Justin Rose.
The South African contingent were slightly off the pace at the Gary Player Country Club with Ernie Els and Open champion Louis Oosthuizen on one under, along with Edoardo Molinari.
Earlier, Fisher was looking good for the overnight lead, but just as lightning and rain arrived to force a two-hour delay, he mishit his tee shot at the par-four 17th and ended with a double-bogey six.
He was on seven under before that, but then slipped to five under with Harrington making the most of the opening.
"It's just one of those things," Fisher said. "I guess six was as good as I could have done.
"At 18 it would have left a sour taste if I ended with five and didn't end with the par. I mean finishing four under would have felt like 76 for the way I played. So I was relieved to have knocked that putt in and five under's a good start."
After the resumption, three-time major winner Harrington sank a 12-foot putt for birdie on 15 to claim the lead. He then had his only blemish of the round on 17, but a fine second shot out of the rough - the ball flew over the trees to within two feet of the cup - allowed him to birdie the last for a one-shot lead.
World No 1 Westwood had made a poor start to the day and was one over through six, before a turn in fortune helped him climb the leaderboard.
"I struggled to hit the greens in the first five or six holes and you know what it's like when you get stuck in the fringes," he said. "You're just not sure how it's going to come out.
"I didn't give myself any birdie chances and then three-putted six.So it was a slow start, but I picked it up after that."
South African Retief Goosen and Dane Anders Hansen were on level par after 72s, while the 12-man line-up was propped up by Tim Clark's 73.
Meanwhile, US Open champion Graeme McDowell has barely had the chance to take stock of a life-changing season after criss-crossing several time zones in a dizzying five-week stretch.
The Ulsterman has competed in European Tour events in Spain, Shanghai, Singapore, Hong Kong and Dubai since the end of October and he is now on the west coast of America for this week's Chevron World Challenge.
"This is my sixth week on the road now - so I've pumped a few air miles," said McDowell on the eve of the tournament at Sherwood Country Club, California "But it's been good. At some point this month I'll sit down and reflect on what's been a life-changing season. I haven't given myself a second to think about what I've achieved this year." McDowell has achieved a great deal, securing a first major title and the winning point at the Ryder Cup in Wales among several other highlights. And it was all made possible 12 months ago when he was given a late entry to the World Challenge after tournament host Tiger Woods withdrew following revelations about his marital infidelities.
McDowell took full advantage of Woods's absence, finishing second, one shot behind winner Jim Furyk, to give his own world ranking a major boost. "There's no doubt, getting the invite from the Tiger Woods Foundation to play here really kind of shaped the start of my season," said the 31-year-old from Portrush.
Collated first round scores in the Sunshine Tour Nedbank Golf Challenge, Gary Player Country Club, Sun City, Johannesburg, South Africa