The 38-year-old Matfield, who has not played international rugby since the 2011 World Cup, will make his 111th appearance, and 18th as captain, at the same time reuniting with Bakkies Botha in an vastly experienced lock pairing.
Also returning to the starting line-up is prop Gurthrö Steenkamp, one of six changes, four positional, to the match-day squad from the team that beat a World XV in Cape Town last week.
Wing Cornal Hendricks will make his test debut, while his provincial team mate from the Cheetahs, uncapped lock Lood de Jager, starts from the bench.
"Cornal performed exceptionally well in his first start for South Africa against the World XV last weekend and really made the most of his opportunity," coach Heyeneke Meyer said in a press release from governing body SARU on Wednesday.
"Lood has everything expected from a modern lock - not only is he big and powerful, but he likes the physical stuff and is very skilful as well."
Centre Jan Serfontein will earn his first test start for the Springboks, alongside JP Pietersen, after Frans Steyn withdrew from the June internationals for personal reasons.
"Jan and JP Pietersen will face a very experienced midfield combination on Saturday, but they have played against the best in Super Rugby and know what is expected of them," Meyer said.
Flank Schalk Burger, who has also not played for the Boks since 2011, is on the bench.
Meyer believes facing Wales will be a real challenge for the side and excellent preparation for this year's Rugby Championship.
"Wales have an experienced coaching team and they were the Six Nations champions in 2012 and 2013, as well as the backbone of the British & Irish Lions team which beat Australia last year, so this will be a massive challenge in our first Test of the season,"
Four players who are part of the squad but not considered for selection because of illness or injury are Juan de Jongh (chest infection), Siya Kolisi (flu), Oupa Mohoje (flu) and Marnitz Boshoff (ankle).
The second match in the two-test series against Wales is in Nelspruit on June 21.
South Africa: 15-Willie le Roux, 14-Cornal Hendricks, 13-JP Pietersen, 12-Jan Serfontein, 11-Bryan Habana, 10-Morné Steyn, 9-Fourie du Preez, 8-Duane Vermeulen, 7-Willem Alberts, 6-Francois Louw, 5-Victor Matfield (captain), 4-Bakkies Botha, 3-Jannie du Plessis, 2-Bismarck du Plessis, 1-Gurthrö Steenkamp.
Substitutes: 16-Schalk Brits, 17-Tendai Mtawarira, 18-Coenie Oosthuizen, 19-Lood de Jager, 20-Schalk Burger, 21-Ruan Pienaar, 22-Johan Goosen, 23-Lwazi Mvovo
- Sports & Recreation
- Cornal Hendricks
- Bakkies Botha