Botha, 34, returns for the first time since the Rugby World Cup in New Zealand in 2011, while prop Gurthrö Steenkamp and hooker Adriaan Strauss will start as well. Eben Etzebeth, Tendai Mtawarira and Bismarck du Plessis drop to the bench.
Willie le Roux takes over at fullback with Pat Lambie shifting to flyhalf in place of Morne Steyn, who is on the bench.
A final call on the availability of Steyn (back) and flank Willem Alberts (shoulder) will be made on Saturday.
If Alberts is unfit to start, Siya Kolisi will take his place on the side of the scrum. Marcell Coetzee has been included on the bench in another rotational change with Kolisi, who will sit out if Alberts is passed fit.
Steyn has been included pending a fitness test on Saturday, with no replacement yet named should he be forced out of the match day 23.
"We said from the start of the tour that we were going to make a few changes for this test," added Meyer.
"We need to keep players fresh and motivated. Willie and Pat both did well after we lost Morné last weekend and deserve another opportunity on Sunday.
"Gurthro and Adriaan, who will take over the vice-captaincy as well, have been part of the squad for a long time and will slot in easily.
"We got our tour off to a good start last week against Wales in Cardiff and the focus this week has been on further improvement in a number of key areas of the game, most notably our discipline."
Winger JP Pietersen will become the 28th player to reach 50 Springbok test caps. The only two other wingers to have reached the milestone are Breyton Paulse and Bryan Habana, with the latter set to make his 92nd appearance on Sunday.
South Africa: 15-Willie le Roux, 14-JP Pietersen, 13-Jaque Fourie, 12-Jean de Villiers (captain), 11-Bryan Habana, 10-Pat Lambie, 9-Fourie du Preez; 8-Duane Vermeulen, 7-Willem Alberts/Siya Kolisi, 6-Francois Louw, 5-Flip van der Merwe, 4-Bakkies Botha, 3-Frans Malherbe, 2-Adriaan Strauss, 1-Gurthrö Steenkamp
Replacements: 16-Bismarck du Plessis, 17-Tendai Mtawarira, 18-Coenie Oosthuizen, 19-Eben Etzebeth, 20-Marcell Coetzee, 21-Ruan Pienaar, 22-Morné Steyn, 23-JJ Engelbrecht
(Reporting by Nick Said in Cape Town; editing by Justin Palmer; nick.said@thomsonreuters.com +27832722948 Messaging nick.said.thomsonreuters.com@reuters.net; To sign up for our Global Sports Forum chatroom, click on https://forms.thomsonreuters.com/global_sports_forum)
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