He chose a new centre partnership with Max Llewellyn and Ben Thomas replacing Eddie James and Joe Hawkins.
Louis Rees-Zammit, who began the first-round victory over Fiji, returns to the right wing in place of Ellis Mee.
In a fourth backline change, Dan Edwards takes over from Sam Costelow as fly-half as Wales seek a second win in South Africa over the Springboks.
Lock Teddy Williams comes in for Ben Carter and flanker Alex Mann gets the nod with James Botham dropping to the bench.
While Wales have five points from two matches, South Africa have 10 through bonus-point victories over England in Johannesburg and Scotland in Pretoria.
"We have made some changes to the starting XV. It is coming to the end of the season and we have had a big bit of travel," said Tandy.
"Some boys deserve an opportunity and it is a chance to freshen up the team.
"South Africa are world champions. They have loads of depth. For us, it is about putting our game out there. We want to see a real physical edge.
"We are going up against probably the most physical team in the world. So we know we are going to have to really step up the physicality.
"It is a great opportunity to test ourselves against the best team in the world."
Wales have faced the Springboks 13 times in South Africa, losing 12 before snatching a 13-12 win in Bloemfontein four years ago.
But the Welsh have less fond memories of the last meeting - a humiliating 73-0 loss in Cardiff last November.
Team (15-1)
Blair Murray; Louis Rees-Zammit, Max Llewellyn, Ben Thomas, Josh Adams; Dan Edwards, Tomos Williams; Aaron Wainwright, Jac Morgan, Alex Mann; Adam Beard, Teddy Williams; Dillon Lewis, Dewi Lake (capt), Rhys Carre
Replacements: Ryan Elias, Nicky Smith, Ben Warren, Freddie Thomas, Tommy Reffell, James Botham, Reuben Morgan-Williams, Joe Hawkins
Coach: Steve Tandy (WAL)