Frans Steyn will start his first Springbok Test at out-half in 14 years while Pieter-Steph du Toit returns to the pack for Saturday's crucial Rugby Championship fixture against Argentina in Durban.
South Africa have been forced to test the depth of their stocks at 10 in recent weeks, with Damian Willemse the latest of their out-halves to become unavailable.
He joins the injured Handre Pollard on the sidelines, while regular back-up Elton Jantjies is unavailable due to personal reasons.
Steyn will now start in the No 10 shirt for the final game of the championship, a role the 35-year-old hasn't played from the start since 2008.
He has been finishing Tests in the position this season and did so as recently as Saturday's 36-20 win in Argentina when Willemse was forced from the field due to injury, but has spent most of his time in a Boks jersey at full-back or centre.
"We were pleased the calmness Frans Steyn brought at fly-half when Damian left the field," South Africa head coach Jacques Nienaber said in naming his side on Tuesday.
Du Toit replaces Franco Mostert at flanker with the latter dropping to the bench as the Boks revert to their favoured 6-2 split between forwards and backs that sees the return of the 'Bomb Squad’ to provide power in the closing stages at King's Park.
"The energy and enthusiasm Pieter-Steph has been showing at training has also been great, and we know what he is capable of in this loose trio," Nienaber said.
It is otherwise an unchanged starting line-up, though hooker Bongi Mbonambi (injury) and wing Kurt-Lee Arendse (suspension) are back among the replacements.
South Africa need to at the very least match the performance of New Zealand against Australia in Auckland earlier on Saturday to stand a chance of winning the Rugby Championship.
Both South Africa and the All Blacks have 14 points in the table, but the latter have a +41 points-difference in matches as opposed to the Boks’ +28, ground that would need to be made up.
"It is all or nothing for us this week, and we have a team with several players who have won the Rugby World Cup and the British & Irish Lions series, so they know it will take nothing less than a quality 80-minute effort to win this match and the competition," Nienaber said.
South Africa: Willie le Roux; Canan Moodie, Jesse Kriel, Damian de Allende, Makazole Mapimpi; Frans Steyn, Jaden Hendrikse; Steven Kitshoff, Malcolm Marx, Frans Malherbe, Eben Etzebeth, Lood de Jager,; Siya Kolisi, Pieter-Steph du Toit, Jasper Wiese.
Replacements: Bongi Mbonambi, Ox Nche, Vincent Koch, Franco Mostert, Duane Vermeulen, Kwagga Smith, Faf de Klerk, Kurt-Lee Arendse.