The 27-year-old Pietersen, who will return from Japan to Durban to play for The Sharks in Super Rugby next season, made his Test debut in 2006 against Australia in Johannesburg when he was only 20.
Pietersen, a Rugby World Cup winner in 2007, would become the fifth player this season to earn his 50th Test cap for South Africa. Only two other wingers, Bryan Habana and Breyton Paulse, have reached this milestone for the Springboks.
"This is really a magnificent achievement for one of the many world-class wingers South African rugby has produced," Springbok coach Heyneke Meyer said.
"For more than seven years, JP has been one of the most consistent players for the Springboks. He always gives everything he has for his country and this is just reward for the hard work and dedication he's put in over the years.
"If not for injuries, JP would probably have played many more Tests for South Africa."
As anticipated, Meyer made a total of five changes to the starting line-up, while two more are possible because of injury niggles.
In the tight five, Bakkies Botha returns for the first time since the Rugby World Cup in New Zealand in 2011, while Gurthro Steenkamp and Adriaan Strauss would start at Murrayfield.
Eben Etzebeth, Tendai Mtawarira and Bismarck du Plessis were on the bench.
In the backline, Willie le Roux takes over at fullback with Pat Lambie shifting to flyhalf. A final call on the availability of Morne Steyn (back) and Willem Alberts (shoulder) would be made on Saturday.
If Alberts was unfit to start, Siya Kolisi would take his place on the side of the scrum.
Marcell Coetzee had been included on the bench in another rotational change with Kolisi, who would sit out if Alberts was passed fit.
Steyn had been included on the bench pending a fitness test on Saturday.
"We said from the start of the tour that we were going to make a few changes for this Test," said Meyer.
"We need to keep players fresh and motivated. Willie and Pat both did well after we lost Morne last weekend and deserve another opportunity on Sunday.
"Gurthro and Adriaan, who will take over the vice-captaincy as well, have been part of the squad for a long time and will slot in easily.
"Furthermore, it has been great to have Bakkies back. His enthusiasm has been contagious and the younger guys have already learned a lot from spending time with him.
"We got our tour off to a good start last week against Wales in Cardiff and the focus this week has been on further improvement in a number of key areas of the game, most notably our discipline. In the Rugby Championship, we conceded the fewest penalties, but last week against Wales we were penalised too much. It's something that is very important to us and we are working very hard on our discipline."
Willie le Roux, JP Pietersen, Jaque Fourie, Jean de Villiers (capt), Bryan Habana, Pat Lambie, Fourie du Preez, Duane Vermeulen, Willem Alberts/Siya Kolisi, Francois Louw, Flip van der Merwe, Bakkies Botha, Frans Malberhe, Adriaan Strauss, Gurthro Steenkamp
Replacements: Bismarck du Plessis, Tendai Mtawarira, Coenie Oosthuizen, Eben Etzebeth, Marcell Coetzee, Ruan Pienaar, Morne Steyn, JJ Engelbrecht.