Rugby World Cup winners Pieter-Steph du Toit and Faf de Klerk will miss the series-deciding third Test against the British and Irish Lions in Cape Town on Saturday due to injury.
Duane Vermeulen, the number eight hoping to make a miraculous comeback after a serious ankle injury, did not make the matchday 23 despite training with the squad on Monday.
Reigning World Rugby Player of the Year Du Toit was ruled out by a shoulder injury sustained after a late tackle from Duhan van der Merwe last Saturday's 27-9 win in the second Test.
His loose forward place goes to Franco Mostert who moves from the second row with Lood de Jager, a replacement in the second Test, coming into the starting XV.
In a surprise move when the team was announced on Tuesday, Cobus Reinach comes in at scrum-half with De Klerk sidelined by a leg muscle strain.
Herschel Jantjies, the reserve scrum-half in the first two Tests, was expected to step up, but remains among the replacements instead.
Head coach Jacques Nienaber has returned to a 5-3 forwards-backs split on the bench having changed to 6-2 after a 22-17 loss in the first Test.
The place vacated by De Jager goes to veteran fly-half Morne Steyn, whose penalty from the halfway line clinched a series victory for the Springboks over the Lions in 2009.
The latest series has seen a number of Springboks celebrate 50th appearances, starting with fly-half Handre Pollard in the first Test.
It was the turn of loosehead prop Steven Kitshoff last weekend and this Saturday inside centre Damian de Allende will reach the milestone.
South Africa: Willie le Roux; Cheslin Kolbe, Lukhanyo Am, Damian de Allende, Makazole Mapimpi; Handre Pollard, Cobus Reinach; Jasper Wiese, Franco Mostert, Siya Kolisi (capt); Lood de Jager, Eben Etzebeth; Frans Malherbe, Bongi Mbonambi, Steven Kitshoff
Replacements: Malcolm Marx, Trevor Nyakane, Vincent Koch, Marco van Staden, Kwagga Smith, Herschel Jantjies, Morne Steyn, Damian Willemse
Coach: Jacques Nienaber (RSA)