The 27-year-old, who has made three substitute appearances for the Boks since making his Test debut in 2010, will pack down at number eight in place of the injured Pierre Spies, who requires surgery on his finger.
Springboks coach Heyneke Meyer said: "Keegan has been playing really well in Super Rugby and he has put up his hand.
"It is a setback losing someone of Pierre's experience but I think that Keegan is the logical choice to replace Pierre. It is a step up and it is in his hands now to see if he can play at this level.
"What you lose in physicality with Keegan you gain with the X-factor he brings to the team."
South Africa's starting line-up shows six changes to the team who drew 14-14 with England in the third Test in June with Morne Steyn retained a fly-half despite criticism about his current form.
South Africa: Kirchner, Mvovo, Villiers (captain), Frans Steyn, Habana, Morne Steyn, Hougaard, Daniel, Alberts, Coetzee, Bekker, Etzebeth, Jannie du Plessis, Bismarck du Plessis, Mtawarira.
Replacements: Strauss, Cilliers, van der Merwe, Potgieter, Pienaar, Lambie, Engelbrecht.
Gilbert has released a new line of rugby cleats. The Gilbert Virtuo 8S is part of the exciting new product. Check it out.
The entire All Blacks apparel line has been updated for 2013/14. Check out the New Zealand All Blacks polo.
The Nike Tiempo is a solid rugby cleat and one of few styles still made from full-grain natural leather.
The Gilbert Blitz 8S rugby cleat is a great cleat at a great price of $69.99. Get a new pair of cleats today.
A cool looking all black rugby cleat with the high performance adidas is known for. Get in the Gear!
Wear the crest of the British and Irish Lions on your t-shirt. A great look for the summer.
The All Blacks Performance t-shirt is black with hints of blue from the training jersey. Very Cool.
The New Zealand All Blacks training jersey for 2013/14. Get in the Gear!
The USA Rugby Pro Alternate rugby jersey is perfect for any fan of the Eagles. Get yours to wear during the summer Test matches.
The NEW All Blacks 2013/14 jersey has arrived at World Rugby Shop. Dare to wear the colors of the All Blacks.