Gio Aplon will take the number 15 shirt at the Nelson Mandela Bay Stadium from Pat Lambie, who has failed to recover from the ankle injury sustained in the second Test last weekend.
Zane Kirchner, who played full-back in the first Test, was also missing from the side named by coach Heyneke Meyer due to a knee injury.
The Springboks, who are looking to wrap up a 3-0 series whitewash, have made two other changes from the side which won in Johannesburg last Saturday.
Uncapped flanker Jacques Potgieter will take over from the injured Willem Alberts while Wynand Olivier will return to the side to replace inside centre Frans Steyn, who is getting married this weekend.
Meyer said: "Injuries have forced us to make a number of changes, which is never ideal, but this provides an opportunity for players like Gio, Wynand and Jacques to put up their hands.
"Gio is our third full-back of the series, but he's experienced and has been part of our planning.
"Wynand came on as a replacement in both of the first two Tests and knows our game plan, while Jacques has impressed this year as a very strong ball-carrier.
"Hopefully he can continue with the good work Willem has done in the last fortnight."
Meyer has included another potential debutant in fly-half Elton Jantjies on the bench. Another change sees Ryan Kankowski take over from Keegan Daniel among the replacements.
Number eight Pierre Spies will win his 50th cap while Meyer has also announced that captain Jean de Villiers, initially appointed for just this series, will continue as skipper throughout the 2012 South African season.
Meyer has himself impressed by making a winning start in his first series but he has warned against complacency.
The former Leicester boss said: "I am happy with the huge strides that have been made in the series but England are not a side that are going to lie down."
South Africa: G Aplon; JP Pietersen, J de Villiers (capt), W Olivier, B Habana; M Steyn, F Hougaard; T Mtawarira, B du Plessis, J du Plessis, E Etzebeth, J Kruger, M Coetzee, J Potgieter, P Spies.
Replacements: A Strauss, W Kruger, F van der Merwe, R Kankowski, R Pienaar, E Jantjies, B Basson.
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