Only lock Eben Etzebeth and winger Ethan Hooker retain their starting roles from the team that beat the All Blacks 43-28 in Baltimore to seal a 3-1 series win in the inaugural Rugby's Greatest Rivalry.
Etzebeth will extend his record as the most capped Springbok of all time to 147 Test matches.
Props Jan-Hendrik Wessels and Zachary Porthen will join forces with hooker Johan Grobbelaar in a new-look front row, while two-time World Cup-winning flyhalf Handre Pollard returns from a calf injury to form a new halves pairing with fit-again scrumhalf Herschel Jantjies.
Centre Andre Esterhuizen has been named skipper, making him South Africa's 68th captain.
Lock Franco Mostert will play his first Test since facing Wales last November.
Despite the mass changes, only three players named in the starting line-up have fewer than 10 Test caps - winger Edwill van der Merwe, lock Paul de Villiers and prop Porthen.
"Australia poses a completely different threat to New Zealand in the way they play, so we believe these combinations would be best suited for the challenge that we will face against them," South Africa coach Rassie Erasmus said.
"This is going to be a big challenge against a team that has been playing good rugby, and who have won four of their last five matches, with their other result being a draw against the Pumas in Argentina."
Erasmus had no second thoughts about allowing veteran duo Pieter-Steph du Toit and Damian de Allende to return home so they could spend time with family.
"They had a heavy workload in the last few months, and they deserve a break," Erasmus said.
"But at the same time we decided from the outset that if everything went according to plan, we would rest them for this match, so it made sense to send them home to spend time with their families."
SOUTH AFRICA: Aphelele Fassi, Edwill van der Merwe, Canan Moodie, Andre Esterhuizen (captain), Ethan Hooker, Handre Pollard, Herschel Jantjies, Marco van Staden, Elrigh Louw, Paul de Villiers, Franco Mostert, Eben Etzebeth, Zachary Porthen, Johan Grobbelaar, Jan-Hendrik Wessels. Replacements: Malcolm Marx, Ox Nche, Wilco Louw, Lood de Jager, Jasper Wiese, Morne van den Berg, Sacha Feinberg-Mngomezulu, Quan Horn.
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