The world's top-ranked player went bogey-free at the Gary Player Country Club, finishing 12 under and three strokes ahead of fellow Englishman Ross Fisher (68).
Edoardo Molinari (67), Miguel Angel Jimenez (69) and overnight leader Padraig Harrington (72) are six off the lead in a tie for third.
Westwood was one off the course record 63, shared by Ernie Els, Henrik Stenson and Nick Watney, to put himself in position for a second tournament win of 2010 and a $1.25 million pay day.
“I played with Henrik when he shot 63 (in 2008), so I was well aware of what the course record was,” Westwood said.
He shot par on No. 2, his only 5 of the round, and birdied No. 3 with a 40-foot putt. He had four birdies on the front nine and four on the back.
“I was in the right spot all day. I played conservative but attacking,” he said. “I made a nice 40-footer on the third which got me going and then really hit it close for the rest of the round … (and) I like these greens.”
Westwood finished with a birdie 3 on the 18th and headed toward the scoring tent, showing no sign of the bothersome right calf injury that interrupted his season.
“I seem to have got into the swing of things now. It was a good day,” he said.
Ireland’s Harrington failed to build on Thursday’s one-shot advantage, scoring a birdie and bogey after he opened with a 66.
“It was a very average day. Didn’t play great, didn’t chip very well and didn’t hole any putts,” said the 2008 PGA Tour and European Tour player of the year, who has slipped to No. 22 in the rankings.
Els, the highest in the field after Westwood at No. 13, shot 68 and trailed by seven shots.