Donald birdied seven of his first 10 holes on the way to a second-round 63 at the Gary Player Country Club and his effort was enough to secure a two-stroke lead over Ross Fisher.
The Englishman, who is without a win in more than a year and has dropped to No 37 in the world, opened the lucrative tournament with a one-under 71 but was soon bang in contention on Friday.
He birdied the first two, picked up another shot at the fourth, made further ground at six and seven and completed a front-nine of 30 with a sixth birdie at the ninth.
A seventh shot was picked up at the 10th and he moved closer to the lead with back-to-back birdies at the 13th, where he was rudely interrupted by a stray baboon on the fairway, and 14th before closing, somewhat disappointingly given the rest of his round, on 10-under with four pars.
He started the day five off the pace set by Fisher, who looked hungry to add to his lead as he opened up with birdies at the third and fourth.
An eagle at the 10th continued his scoring assault and when he birdied 11 as well, it seemed unlikely even Donald would be able to deny Fisher the halfway lead.
But a poor tee-shot at the 12th cost Fisher a double bogey, also sending Donald to the top of the leaderboard, and he dropped a further shot at the long 14th to finish on eight-under.
There are another two strokes back to third-placed Frenchman Alexander Levy, who matched Fisher’s round of 70 and struggled bar a run of three successive birdies from the 10th.
Danny Willett moved up to fourth with a bogey-free round of 68 but it was a frustrating day in the final group for Marcel Siem, who failed to make the most of a decent start in his level-par round of 72.
The German looked to be in position to challenge when he added to an eagle at the second with successive birdies at six and seven, but he would go on to make a bogey at the eighth and drop two more shots coming home.
Home favourite George Coetzee also struggled on day two, mixing in five bogeys with only three birdies to drop into a tie for 11th alongside Lee Westwood, one stroke behind leading South African players Charl Schwartzel and Tim Clark.
The field was also reduced to 29 with Ryder Cup hero Jamie Donaldson pulling out of the tournament before the start of the second round, citing a serious migraine for his decision.
Watch third round coverage of the Nedbank Golf Challenge live on Sports 4 HD from 8:00am on Saturday.