McKenzie went with Matt Toomua for his first two matches in charge - back-to-back defeats to the All Blacks - but has reverted to the number 10 who helped him to Super Rugby success at the Queensland Reds for the clash with the Springboks.
Israel Folau will make his first start for Australia at full-back after being moved from the wing in place of Jesse Mogg in an effort to get him more involved in the game.
Nick Cummins replaces Folau on the wing, while Sekope Kepu comes in for Ben Alexander at tighthead prop and uncapped Jake Schatz is named on the bench in place of his fellow Queensland loose forward Liam Gill.
Cooper has not started a test match since last September's match against Argentina with first injury and then a falling-out with previous Wallabies coach Robbie Deans keeping him out of international rugby.
The 25-year-old's unpredictability can also be a liability but he has started seven tests against South Africa and won six of them, including the last five.
"We have very specific thoughts about how we want to play this game and feel Quade is best suited to carrying that out," McKenzie said.
"It has been almost 12 months since he last started a test match and I'm sure there were times where he wondered if he would wear the number 10 jersey again. He's worked really hard both on and off the field to now get that chance.
"He's carried himself extremely well all year and during the last fortnight in the role we've asked him to complete. Now, he gets a chance to make an impact from the start of the game."
Despite playing full-back in Super Rugby, Folau has started all five of his tests on the wing but has not been as involved as many would like after an explosive two-try debut against the British and Irish Lions.
Cummins, who adopted the nickname "honey badger" because of the animal's ferocity when attacked, is a big man with an eye for the tryline who was perhaps unlucky not to get a run-out in against the Lions.
"Israel has played more full-back than on the wing so he will undoubtedly feel comfortable playing the position," said McKenzie.
"Once we made the decision to move Israel it opened the door for another player on the wing. The Springboks are an abrasive and physical team and we feel Nick's style of play will suit that."
With Ben Alexander following Benn Robinson out of the starting line-up, McKenzie has now done away with the props who formed the bedrock of the Australia scrum under Deans.
"Up front Keps has been on the fringes but he is a very good technician of the game, which is important as everyone continues to work out the new scrum laws," McKenzie concluded.
"We've got a lot of good players in this space and for this week Keps deserves an opportunity to start."
Leaving out Gill, one of the best young openside flankers in the world, in favour of Queensland Player of the Year Schatz would appear to be another "horses for courses" selection against the physically imposing South Africans.
Team: 15-Israel Folau, 14-Nick Cummins, 13-Adam Ashley-Cooper, 12-Christian Leali'ifano, 11-James O'Connor, 10-Quade Cooper, 9-Will Genia, 8-Ben Mowen, 7-Michael Hooper, 6-Scott Fardy, 5-James Horwill (captain), 4-Rob Simmons, 3-Sekope Kepu, 2-Stephen Moore, 1-James Slipper
Replacements: 16-Saia Fainga'a, 17-Scott Sio, 18-Ben Alexander, 19-Kane Douglas, 20-Jake Schatz, 21-Nic White, 22-Matt Toomua, 23-Jesse Mogg