Number eight Duane Vermeulen will make his Springbok debut when the South Africans tackle Australia in Perth on Saturday.
Cheetahs fly-half Johan Goosen has been selected on the bench and will also earn his first Springbok cap if he gets game time at Paterson's Stadium.
Adriaan Strauss has been included at hooker after coming through a first set of fitness tests, but he will be given until Friday to fully shake his knee injury.
Vermeulen's inclusion at the back of the scrum is one of five changes from the starting team that played Argentina in Mendoza. Two of these changes are positional, with Francois Hougaard moving from scrum-half to left wing and Willem Alberts shifting from number eight to flank.
Other changes in the pack sees Juandré Kruger return as the starting lock, while Andries Bekker - who played his worst game for the Boks last week - drops out completely along with Jacques Potgieter.
In-form scrum-half Ruan Pienaar is favoured at number nine will start his first Test of 2012. This has resulted in two further changes to the bench - Bath flank Francois Louw has been included in the match 22 for the first time this season, while speedster Lwazi Mvovo is also amongst the replacements after making way for Hougaard.
"We've decided to put Duane straight into the starting team because he is a classic number eight, a position we've lacked in since Pierre Spies got injured and Ryan Kankowski moved to Japan," said Springbok coach Heyneke Meyer.
"I've always admired the way Duane plays rugby and he's fitted in very well the past week. He would've been a Springbok years ago if it had not been for injuries and it's great to finally see him selected.
"The same goes for Johan, who in my mind can become one of the great fly-halves in world rugby. I've been very impressed with his work ethic and attitude since he joined the squad on Thursday in Johannesburg and we will keep on managing him carefully over the next few weeks."
The Springbok team boast a total of 451 Test caps: 339 of those are in the back-line, while the forwards have 112 caps - one more than the total of Springbok caps accumulated by former captain John Smit in his career.
South Africa: 15 Zane Kirchner, 14 Bryan Habana, 13 Jean de Villiers (c), 12 Frans Steyn, 11 Francois Hougaard 10 Morné Steyn, 9 Ruan Pienaar, 8 Duane Vermeulen, 7 Willem Alberts, 6 Marcell Coetzee, 5 Juandre Kruger, 4 Eben Etzebeth, 3 Jannie du Plessis, 2 Adriaan Strauss, 1 Beast Mtawarira.
Replacements: 16 Tiaan Liebenberg, 17 Pat Cilliers, 18 Flip van der Merwe, 19 Francois Louw, 20 Johan Goosen, 21 Pat Lambie, 22 Lwazi Mvovo.
Date: Saturday, September 8
Venue: Paterson's Stadium, Perth
Kick-off: 18:00 (12:00 SA time; 10:00 GMT)
Referee: Nigel Owens (Wales)
Assistant referees: Wayne Barnes (England), Glen Jackson (New Zealand)
TMO: Matt Goddard (Australia)