Pietersen replaces Lwazi Mvovo and Bryan Habana is back on the left wing.
Coach Heyneke Meyer has also made four changes to his replacements from the squad that beat the United States 64-0.
Veteran lock Victor Matfield has failed to regain fitness following a hamstring injury.
Hooker Adriaan Strauss, prop Jannie du Plessis, scrum-half Ruan Pienaar and fly-half Pat Lambie are back on the Springboks' bench.
Meyer said Pietersen and Habana "have been in superb form" with nine tournament tries between them.
Habana is also on the brink of overtaking New Zealand legend Jonah Lomu as the top try-scorer in World Cup history.
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"They are playing some of the best rugby of their lives," said Meyer.
"They have been scoring some wonderful tries, as has Lwazi Mvovo, so it's really great to know that there is good competition among the wings.
"It made sense to reunite Bryan and JP on the wing as it brings a lot of experience to our backline, which has been doing well despite the relative inexperience of Handré Pollard, Damian De Allende and Jesse Kriel."
Meyer also backed the experienced returnees to South Africa's bench.
"We've seen first-hand how important it is to have experienced players on the field at the end of a match and to have this kind of experience available on the bench in a knock-out match is great," said Meyer.
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"Saturday's match will be huge and we are expecting an arm wrestle right until the end.
"We're playing against a well-balanced side that always likes to mix things up when it comes to physicality.
"They have a good set piece and some strong ball carriers upfront and in the back - it's what you expect to face at this stage of the competition and we're very excited about the challenge."
Backs: Willie le Roux; JP Pietersen, Jesse Kriel, Damien de Allende, Bryan Habana; Handre Pollard, Fourie du Preez (capt).
Forwards: Tendai Mtawarira, Bismarck du Plessis, Frans Malherbe, Lodewyk de Jager, Eben Etzebeth, Schalk Burger, Duane Vermeulen,  Francois Louw.
Replacements: Adriaan Strauss, Trevor Nyakane, Jannie du Plessis, Pieter-Steph du Toit, Willem Alberts, Ruan Pienaar, Pat Lambie, Jan Serfontein
South Africa have made one change to their starting line-up as wing JP Pietersen returns to face Wales in Saturday's World Cup quarter-final at Twickenham.