First five-eighths Handré Pollard and Elton Jantjies, flanker Pieter-Steph du Toit and centre Lukhanyo Am are all injured.
Pollard and Am will play no part in the second half of the Championship. They have returned to their respective Leicester and Natal clubs for assessment of their injuries.
Damian Willemse replaces Pollard, while Jesse Kriel will play at centre.
Youthful wing Canan Moodie, 19, will debut on the wing with Jaden Hendrikse preferred at halfback, with Cobus Reinach as his back-up, and Franco Mostert has been named on the blindside flank while Jasper Wiese has replaced Duane Vermeulen at No8.
Springboks coach Jacques Nienaber said: "Damian possesses a specific skill set.
"And that's what he needs to bring to this game. We're always telling the players there is a broad game plan to be followed, but you have the freedom to stamp your own authority on it.
"We call it bringing one's 'circus act to the party'. That's what we're expecting from him."
Nienaber said the Test would be a good opportunity for Moodie.
"He was a stand-out player for the Bulls this season in the United Rugby Championship. He's a very talented player, who will enjoy this opportunity."
Kriel said he wasn't feeling any pressure in taking on the centre role from arguably the best Springbok of the season in Am.
"Lukhanyo has set a great standard. He has been playing amazing rugby. I know what role and responsibilities I have to do in my position to contribute to the team. I am looking forward to the challenge."
South Africa, who sit at the bottom of the Championship ladder, will play the game as if it was a Cup final.
Nienaber said: "This week is a final for us to stay in the competition, and we expect Australia to be desperate, but so are we.
"We let ourselves down in the last two games, and we are determined to rectify that and change our fortunes in Australia. We'll prepare as well as possible this week to stay in the hunt for the title."