Wales will be without captain Alun Wyn Jones and loose-forward Ross Moriarty for the remainder of the autumn international series after they were ruled out for "a number of months" on Tuesday.
Welsh Rugby confirmed the pair will both need surgery - lock Jones for his troublesome shoulder and Moriarty after he was injured in the 54-16 mauling by New Zealand on Saturday.
Back-rower Taulupe Faletau was the third player sidelined for the remainder of the series this month, due to an ankle injury.
The trio will miss the games against South Africa on Saturday, and then Fiji and Australia on consecutive weekends after that.
Shane Lewis-Hughes, who can play lock or as part of the back row, and uncapped lock Rhys Davies have been called into the squad.
Halfback Tomas Williams believes Wales have leaders in their squad to step into Jones's shoes for the next three tests.
"Obviously, he'll be a big loss. He's a big leader, but other boys will have to step up," Williams told reporters on Tuesday.
Better news for coach Wayne Pivac is the return from COVID-19 isolation of centre Willis Halaholo.
The Springboks have injury worries of their own, selecting Herschel Jantjies in place of sidelined No.9 Faf de Klerk, in one of three changes to the XV that beat the All Blacks last month.
With Jantjies promoted, Cobus Reinach was added in the only change to the reserves.
"I don't know if it will change their game plan too much," Williams said.
"They will be physical, there are no ifs or buts about that. But we are confident we can match that."
South Africa will field a revamped backline featuring fullback Damian Willemse and winger Jesse Kriel against Wales at Principality Stadium.
"It is important to give Damian and Herschel game time to develop and measure themselves in starting roles," coach Jacques Nienaber said on Tuesday.
"Jesse has also been training hard; he is very experienced and he brings the physicality that will be necessary against Wales."
South Africa: Damian Willemse, Jesse Kriel, Lukhanyo Am, Damian de Allende, Makazole Mapimpi, Handre Pollard, Herschel Jantjies; Duane Vermeulen, Kwagga Smith, Siya Kolisi (capt), Lood de Jager, Eben Etzebeth, Trevor Nyakane, Bongi Mbonambi, Ox Nche. Res: Malcolm Marx, Steven Kitshoff, Vincent Koch, Franco Mostert, Jasper Wiese, Cobus Reinach, Elton Jantjies, Frans Steyn.