Veteran wing Bryan Habana has been dropped after South Africa coach Allister Coetzee opted to select a new-look backline for Saturday's clash with Wales in Cardiff.
Jamba Ulengo is poised to debut in place of Habana, who has been omitted from the squad altogether, and the Bulls man will be joined in the backs by another debutant Rohan Janse van Rensburg, who has been named at inside-centre.
Faf de Klerk and Elton Jantjies have been restored as the halfback pairing and Johan Goosen replaces Willie le Roux at fullback.
With a combined total of just 40 caps, the back division will be the most inexperienced fielded by South Africa since 1994.
Up front, meanwhile, a neck injury to Willem Alberts means that dynamic Cheetahs flanker Uzair Cassiem will also make his first Test appearance and he will be joined in the pack by Sharks prop Lourens Adriaanse. Back-rower Jean-Luc du Preez is poised to become the visitors' fourth debutant of the day should he be introduced from the bench.
The Springboks will be looking to bounce back from a first defeat to Italy, a result that prompted Coetzee to issue a public apology.
But the embattled coach is hopeful that his players have what it takes to maintain their dominance over Wales that has seen them win 17 of the last 18 meetings between the two countries.
"We have a less experienced team but I want to see some energy and an improved performance," he said. "Our selection is also keeping in mind of the process and necessity to build towards 2019.
"There is only one way for us to go from here. We are starting from ground zero, and we can only go up. I have seen the intent and enthusiasm showed by the newcomers this week and I am hoping it will pay off with a good performance on match day. It has been a difficult week but there is a lot of excitement around the team."
South Africa have lost seven Tests this year and their defeat against Italy saw them drop out of the top four in the world rankings for the first time in 10 years.
South Africa: Johan Goosen, Ruan Combrinck, Francois Venter, Rohan Janse van Rensburg, Jamba Ulengo, Elton Jantjies, Faf de Klerk; Tendai Mtawarira, Adriaan Strauss, Lourens Adriaanse, Pieter-Steph du Toit, Lood de Jager, Nizaam Carr, Uzair Cassiem, Warren Whiteley.
Replacements: Malcolm Marx, Steven Kitshoff, Trevor Nyakane, Franco Mostert, Jean-Luc du Preez, Piet van Zyl, Pat Lambie, Lionel Mapoe.