Handre Pollard will receive his first South Africa cap when he starts at fly-half against Scotland in Port Elizabeth on Saturday.
The IRB Junior World Player of the Year is one of five uncapped players in Heyneke Meyer's match-day squad.
There are six changes to the Springboks' XV that started last weekend's 31-30 win against Wales.
Winger Lwazi Mvovo and flanker Schalk Burger are among those coming into the hosts' starting line-up.
Lock Lood de Jager, back-row Marcell Coetzee and prop Coenie Oosthuizen also return to the team.
Pollard, 20, captained South Africa to second place at the Junior World Cup in New Zealand, losing out in the final to England last week.
"Handre is a very talented player and has a big opportunity this week, but he'll have (scrum-half) Fourie du Preez's experience next to him, while he's played a lot with (centre) Jan Serfontein before," said head coach Meyer.
"Our plans had always been to try a few new combinations this week against Scotland and I'm looking forward to see the guys grab their opportunities."
The four uncapped players on the bench are prop Marcel van der Merwe, lock Stephan Lewies, loose-forward Teboho Mohoje and fly-half Marnitz Boshoff.
Meyer released seven of his overseas-based players following the 2-0 series win over Wales, including winger Bryan Habana.
Scotland failed to score a point in their last meeting with the Springboks, the visitors powering to a 28-0 success at Murrayfield last November.
South Africa: Willie le Roux, Cornal Hendricks, JP Pietersen, Jan Serfontein, Lwazi Mvovo, Handre Pollard, Fourie du Preez, Duane Vermeulen, Schalk Burger, Marcel Coetzee, Victor Matfield (captain), Lood de Jager, Jannie du Plessis, Bismarck du Plessis, Coenie Oosthuizen.
Replacements: Adriaan Strauss, Trevor Nyakane, Marcel van der Merwe, Stephan Lewies, Oupa Mohoje, Francois Hougaard, Marnitz Boshoff, Zane Kirchner.