South Africa expect "a hard grind of a Test" against Wales on Saturday.
Damian Willemse replaces Willie le Roux at full-back and centre Jesse Kriel comes in for S'bu Nkosi on the wing.
Scrum-half Herschel Jantjies replaces the injured Faf de Klerk as the third change from last month's 31-29 win over New Zealand.
World champions South Africa play Wales at the Principality Stadium in Cardiff before facing Scotland and England on the following weekends.
They come into the series having beaten New Zealand in a thrilling finale of the Rugby Championship in October, while a depleted Wales suffered a 54-16 defeat by the All Blacks in the first of their autumn Tests.
The Springboks have not won in Cardiff since 2013, although they have beaten Wales in the knockout stages of the last two World Cups.
"Wales are a tough side to beat and our track record over here in the last few years is evidence of that," said Springboks head coach Jacques Nienaber.
"We also edged them in the [2019] Rugby World Cup semi-final, so we know that this is going to be a hard grind of a Test.
"They may have lost against the All Blacks last week but this result was in the absence of a number of key players, so this week will be a completely different proposition."
Willemse comes in for Le Roux in what is described as a "rotational switch", while Jantjies takes over from De Klerk who was ruled out of the squad due to a hip flexor injury.
Kriel replaces Nkosi, who South Africa say is yet to travel to the UK as he awaits the necessary paperwork.
Wales welcome back their England-based contingent, but await news on the fitness of captain Alun Wyn Jones and Ross Moriarty, who both left the field on Saturday with shoulder injuries, while Dan Biggar is also a concern having limped off during Northampton's defeat by Leicester.
Under previous head coach Warren Gatland, Wales' matches against South Africa were often tight and physical affairs.
Saturday's meeting with the Springboks will be Wales' first under Wayne Pivac, who has introduced a more attacking style since succeeding Gatland after the 2019 World Cup.
"The Wales that I saw in the Six Nations [earlier this year, which Wales on] was pretty much what I saw from Wales in World Cup 2019," said Nienaber.
"The Wales that I saw with younger players playing against Canada and then the two Tests against Argentina [in July], I saw a little bit of a different style of play.
"Then last weekend against New Zealand, I saw probably two halves.
"I think they are in a place of transition and I think they will probably play the style the conditions allow, and the style that we allow. They're a pretty adaptable side."
South Africa: Damian Willemse; Jesse Kriel, Lukhanyo Am, Damian de Allende, Makazole Mapimpi; Handre Pollard, Herschel Jantjies; Ox Nche, Bongi Mbonambi, Trevor Nyakane, Eben Etzebeth, Lood De Jager, Siya Kolisi (capt), Kwagga Smith, Duane Vermeulen.
Replacements: Malcolm Marx, Steven Kitshoff, Vincent Koch, Franco Mostert, Jasper Wiese, Cobus Reinach, Elton Jantjies, Frans Steyn.
Wales Autumn internationals XV
Pick your starting XV for Wales' second Autumn series game against South Africa