Fly-half Handre Pollard and scrum-half Cobus Reinach will start for South Africa against England on Saturday.
Pollard, who scored 22 points in the Springboks' 32-12 World Cup final win against England in 2019, takes Elton Jantjies' starting spot.
Reinach replaces Herschel Jantjies, while Lood de Jager starts at lock in place of Franco Mostert.
The Twickenham encounter will be South Africa's final match of the autumn after victories in Wales and Scotland.
Springboks coach Jacques Nienaber said he had made changes to his starting XV because "England will pose different threats to Scotland".
Reinach makes his first Test start since August in the continued absence of injured scrum-half Faf de Klerk, while star wing Cheslin Kolbe has also missed the autumn Tests through injury.
Nienaber added: "Elton, Herschel and Franco have shown they can inject energy and ignite a spark on attack off the bench, which will be handy against an English outfit we know will be highly charged up for this match."
England will be without hooker Jamie George and captain Owen Farrell because of injuries sustained in last Saturday's 32-15 win against Australia.
But, with new faces brought into the side as head coach Eddie Jones builds a team for the 2023 World Cup and the introduction of attack coach Martin Gleeson, Nienaber is expecting different challenges to those posed in the World Cup final.
The Springboks coach said: "England have traditionally had a strong pack of forwards and backs that can trigger action on attack, but they have a number of new players and coaches this season, who will want to make their mark, so there may be a different dynamic in their style of play."
England's team is due to be named at 13:30 GMT on Thursday.
South Africa: Le Roux; Kriel, Am, De Allende, Mapimpi; Pollard, Reinach; Nche, Mbonambi, Nyakane, Etzebeth, De Jager, Kolisi, Smith, Vermeulen.
Replacements: Marx, Kitshoff, Koch, Mostert, Wiese, H Jantjies, E Jantjies, Steyn.