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Heyneke Meyer dropped Morne Steyn - the second highest points scorer in Springbok Test history - for 20-year-old newcomer Johan Goosen for Saturday's match at Loftus Versfeld.
Robbie Deans opted to start recently out-of-form fullback Kurtley Beale at No 10 for Australia in place of the injured and controversial Quade Cooper.
While Cooper's criticism of Australia's team environment under Deans continued from the sidelines, Meyer hoped to silence his doubters by replacing Steyn, who had played 30 straight Tests and around whom South Africa had built its game, with Goosen for the youngster's first Test start.
Beale will wear the No 10 jersey for the first time for Australia.
"Call it a gamble if you like," Deans said of both changes. "Call it a desire to get the result. If you don't chance anything, you won't get anything."
Deans may already be on his way out, with Cooper's Reds coach Ewen McKenzie ready to take over the Australia job next year.
Meyer's appointment was backed by a wave of public approval in South Africa at the start of the year but has already been placed under pressure seven games in after Steyn's lackluster displays contributed to a losing tour of Australasia.
"It feels sometimes it's life and death decisions. I know this is only a game but for me this is not only a game," Meyer said this week, showing the country's sometimes ruthless rugby followers that he cared as much as they did.
In the context of the inaugural four-nation Rugby Championship following Argentina's introduction, South Africa and Australia are likely playing for second behind the runaway tournament leader and world champion, New Zealand.
But the game is a potential watershed moment for both.
An historic first victory for Australia at Loftus, the high-altitude stadium in Pretoria where South Africa rarely loses, would heavily strengthen Deans' hand and likely undermine Cooper's comments referring to a "toxic" environment in the squad which was "destroying" him as a person and a player.
A Wallabies win could see the end of Cooper's Test career.
"It's never the case," Wallaby hooker Tatafu Polota-Nau said in response to Cooper's complaints of an unhappy group.
A South African victory is expected, but would reinvigorate Meyer's young reign and give the Springboks a new playmaker to build future teams around in the highly rated Goosen.
That would also limit Steyn's future involvement in the South African setup.
The selections of Beale and Goosen both suggest an open, expansive game on the South African highveld, where the countries racked up over 70 points in both of their meetings in 2010.
"I think you'll see a bit of everything. I don't think it will be one-dimensional," Deans said.
Meyer agreed, with more running expected from the Boks under Goosen than the kicking-orientated Steyn.
"We've changed a few things. Obviously you want the guys to score tries and go out there and express themselves so hopefully things will click," Meyer said. "I've a good feeling about this team."
Up front, Australia captain and lock Nathan Sharpe will play his 110th Test, equaling the Wallaby appearance record for a forward. Second rower Eben Etzebeth returns to strengthen South Africa's pack after a two week ban for a head-butt on Sharpe in Australia's victory in Perth.
Teams:
South Africa:
15 Zane Kirchner, 14 Bryan Habana, 13 Jean de Villiers (captain), 12 Francois Steyn/Jaco Taute, 11 Francois Hougaard, 10 Johan Goosen, 9 Ruan Pienaar, 8 Duane Vermeulen, 7 Willem Alberts, 6 Francois Louw, 5 Andries Bekker, 4 Eben Etzebeth, 3 Jannie du Plessis, 2 Adriaan Strauss, 1 Beast Mtawarira
Substitutes: 16 Tiaan Liebenberg, 17 Coenie Oosthuizen, 18 Flip van der Merwe, 19 Marcell Coetzee, 20 Elton Jantjies, 21 Jaco Taute/Juan de Jongh, 22 Patrick Lambie
Australia:
15
Berrick Barnes, 14 Dominic Shipperley, 13 Adam Ashley-Cooper, 12 Pat
McCabe, 11 Digby Ioane, 10 Kurtley Beale, 9 Nick Phipps, 8 Radike Samo, 7
Michael Hooper, 6 Dave Dennis, 5 Nathan Sharpe (captain), 4 Kane
Douglas, 3 Ben Alexander, 2 Tatafu Polota Nau, 1 Benn Robinson
Substitutes:
16 Saia Fainga'a, 17 James Slipper, 18 Rob Simmons, 19 Scott
Higginbotham, 20 Liam Gill, 21 Brett Sheehan, 22 Anthony Fainga'a
