The 24-year-old flanker has been given the nod ahead of Schalk Burger to replace the injured Francois Louw in one of three changes to the Springboks' starting line-up for the game at Newlands.
Mohoje, who has just one appearance in Test rugby to his name as a replacement against Scotland in June, comes in along with scrum-half Francois Hougaard - who makes his first start since 2012 in the absence of the injured Ruan Pienaar.
Marcell Coetzee moves to number six, with Duane Vermeulen starting at number eight and coach Heyneke Meyer also makes four alterations on the bench.
Scrum-half Cobus Reinach is poised to make his debut after being named among the replacements, while the experienced Burger, lock Bakkies Botha and wing JP Pietersen will also start on the bench.
Meyer said: "Injuries forced our hand with Francois [Louw] and Ruan Pienaar not available, but Hougie [Hougaard] and Oupa [Mohoje] have been part of the squad for the entire season and I've got the utmost confidence in them making the step up.
"Francois [Hougaard] brings different strengths to the team at number nine and has an opportunity to demonstrate the contribution he can make on Saturday, while Oupa is more of a traditional blindside flanker who will get another opportunity to show what he can do in his breakthrough season.
"He has really come on in leaps and bounds this season and responded to the goals set for him."
South Africa, who along with their opponents sit six points behind New Zealand in the standings, have not lost to Australia at Newlands in 22 years.
South Africa team: Willie le Roux, Cornal Hendricks, Jan Serfontein, Jean de Villiers [captain], Bryan Habana, Handre Pollard, Francois Hougaard, Duane Vermeulen, Teboho Mohoje, Marcell Coetzee, Victor Matfield, Eben Etzebeth, Jannie du Plessis, Adriaan Strauss, Tendai Mtawarira.
Replacements: Bismarck du Plessis, Trevor Nyakane, Marcel van der Merwe, Bakkies Botha, Schalk Burger, Cobus Reinach, Pat Lambie, JP Pietersen