Kolisi and Etzebeth return from injury, as does mercurial flyhalf Sacha Feinberg-Mngomezulu, who will also make his first Springboks appearance of the year.
Wing Ethan Hooker and centre Andre Esterhuizen are also back in the mix, with scrumhalf Cobus Reinach capping off a backline packed with power and pace.
Number eight Cameron Hanekom and flanker Elrigh Louw round off the back row with Kolisi, while Etzebeth will be partnered by another returning veteran in Lood de Jager, who will hope to put persistent shoulder injuries behind him.
Johan Grobbelaar is at hooker with props Boan Venter and Thomas du Toit either side of him.
Coach Rassie Erasmus has chosen a 6-2 split between forwards and backs on the bench, with flyhalf Handre Pollard included along with scrumhalf Morne van den Berg.
"This match is the perfect occasion for players like Siya, Eben, Lood, Sacha, Morne and the other players returning from injury to get a tough Test under the belt and get back into full swing at international level, as Argentina are a formidable team, who will push us to the limit," said Erasmus.
"The guys have been working very hard to return from injury and there is no better test to measure where they are than facing the Pumas in Argentina.
"The other players in the squad also all deserve their places and have been waiting patiently as we tested combinations in the last few matches, and one can sense the excitement in the group to get back onto the field."
Both sides are missing a host of players but Erasmus is expected a tough encounter from their hosts.
"The Argentineans are very similar to South Africans in many ways. Their passion and patriotism for their country and people, and the way they give everything on the field and keep fighting is a testament to the type of Test match we are expecting this weekend," he said.
"They have beaten us twice in Argentina before and they delivered brave performances in their Nations Championship matches, and will have a point to prove on Saturday, so we are fully aware of the challenge ahead."
Springbok team: 15-Aphelele Fassi, 14-Edwill van der Merwe, 13-Canan Moodie, 12-Andre Esterhuizen, 11-Ethan Hooker, 10-Sacha Feinberg-Mngomezulu, 9-Cobus Reinach, 8-Cameron Hanekom, 7-Elrigh Louw, 6-Siya Kolisi, 5-Lood de Jager, 4-Eben Etzebeth, 3-Thomas du Toit, 2-Johan Grobbelaar, 1-Boan Venter.
Replacements: 16-Jan-Hendrik Wessels, 17-Gerhard Steenekamp, 18-Zachary Porthen, 19-Ben-Jason Dixon, 20-Cobus Wiese, 21-Marco van Staden, 22-Morne van den Berg, 23-Handre Pollard.