Meanwhile prop Scott Andrews will start his first rugby test in four-and-a-half years.
The Springboks have also made five changes, handing first starts to Sharks No 8 Dan du Preez and Bulls wing Warrick Gelant.
Andrews and No 8 Taulupe Faletau were the only non-Wales-based players in their team.
Faletau has a release clause for Wales tests in his contract with English club Bath, where Andrews is on loan from the Cardiff Blues.
Because the test is outside the autumn international window, Wales has had to let prop Tomas Francis, first five-eighth Rhys Priestland, and centers Owen Williams, and Jamie Roberts return to their English clubs.
Wales coach Warren Gatland didn't know on Thursday why Faletau was the exception.
"I'm not really clear on it," Gatland said. "All I know is that he's told us he's available for this game. I don't know what agreements all the players have with the clubs."
Bath risk a hefty fine from England club overseers, who have a blanket ban on non-England players playing tests outside of the window.
Parkes qualifies for Wales when he completes three years' residency on Sunday, and has been part of the squad in anticipation of his availability. But he has a start because the likes of Williams, Roberts and Jonathan Davies are unavailable. He also fits in the playmaker mould Gatland wants at second five-eighth.
Parkes played Super Rugby for the Blues, Southern Kings, and Hurricanes, then followed his former Auckland coach Wayne Pivac to Scarlets in 2014. He will partner clubmate Scott Williams in midfield, and have three other Scarlets in the backline.
Among them halfback Aled Davies.
Rhys Webb was the No 9 against New Zealand last weekend, but his head hit the ground hard in a tackle and he was taken off after 10 minutes. He didn't train fully until Thursday and is in the reserves.
Gareth Davies substituted for Webb and was expected to start against the Springboks, but he's been carrying a shoulder injury and has been rested, meaning Aled Davies, who made his debut in June, will start his biggest match.
The front row has also been problematic. Injuries or club commitments removed Samson Lee, Francis, and Leon Brown from tighthead prop consideration, and Gatland recalled Andrews for his first appearance since November 2016 against Japan.
Kristian Dacey starts at hooker for Ken Owens, who hurt his back, and the fifth change from the lineup which lost to the All Blacks 33-18 has Cory Hill locking with captain Alun Wyn Jones in place of Jake Ball, who needed surgery after dislocating a shoulder.
"We've had 11 injuries in this campaign," Gatland said. "We're down to about 25 from the original squad we picked. It's been a challenge [choosing a team]."
The reserves were shaken up, with only prop Wyn Jones retained. Forwards Elliot Dee, Rhodri Jones, Seb Davies, and Dan Lydiate have come in along with backs Webb, Rhys Patchell, and Owen Watkin.
Gelant made his Springboks debut last weekend as Italy was beaten 35-6 and starts in place of Courtnall Skosan. Du Preez comes in after Duane Vermuelen had to return to his Toulon club.
Openside flanker Francois Louw also had to go back to Bath, and Siya Kolisi starts in his place after missing the Italy test for the birth of his second child.
Loosehead prop Steven Kitshoff is in after Tendai Mtawarira failed to recover from a groin injury, and hooker Malcolm Marx is back fully fit after hurting his shoulder against France, dropping Bongi Mbonambi to the bench after an impressive effort against Italy.
Two Sharks could make their debuts from the reserves: Scrumhalf Louis Schreuder and center Lukhanyo Am.
South Africa has lost its last two tests to Wales in Cardiff. It has never lost twice in a row to the Welsh.
Lineups:
Wales: Leigh Halfpenny, Hallam Amos, Scott Williams, Hadleigh Parkes, Steff Evans, Dan Biggar, Aled Davies; Taulupe Faletau, Josh Navidi, Aaron Shingler, Alun Wyn Jones (captain), Cory Hill, Scott Andrews, Kristian Dacey, Rob Evans. Reserves: Elliot Dee, Wyn Jones, Rhodri Jones, Seb Davies, Dan Lydiate, Rhys Webb, Rhys Patchell, Owen Watkin.
South Africa: Andries Coetzee, Dillyn Leyds, Jesse Kriel, Francois Venter, Warrick Gelant, Handre Pollard, Ross Cronje; Dan du Preez, Pieter-Steph du Toit, Siya Kolisi, Lood de Jager, Eben Etzebeth (captain), Wilco Louw, Malcolm Marx, Steven Kitshoff. Reserves: Bongi Mbonambi, Trevor Nyakane, Ruan Dreyer, Oupa Mohoje, Uzair Cassiem, Louis Schreuder, Elton Jantjies, Lukhanyo Am.