Willemse moves from full back to fly half and will take over the kicking duties, as Nienaber named all four of his scrum halves in the matchday 23.
Cobus Reinach (33) starts in the number nine jersey, while the electric Grant Williams (27) will play on the wing. Jaden Hendrikse (23) and Faf de Klerk (31) are on the bench.
"Grant played school rugby on the wing, and he has come on at wing before for us, so we are excited to give him this opportunity to start there and for him to gain international experience in the position," Nienaber said.
"Faf is also one of our back up flyhalves in the squad, and the same applies to him, as it will be valuable for him and the team to get some game time in the position."
There is a return from injury for Canan Moodie (20), who is at outside centre, with lock Jean Kleyn (30) also overcoming a niggle to start. The team will be captained by hooker Bongi Mbonambi (32).
The wholesale changes were not unexpected as Nienaber seeks to both rest those that featured in a bruising battle with Scotland, and also give minutes to his wider squad.
Willie le Roux (34) slots in at full back, with 2019 World Cup winner Makazole Mapimpi (33) on the wing with Williams. Andre Esterhuizen (29) partners Moodie in the midfield.
Veteran number eight Duane Vermeulen (37) is part of a back row of the scrum that also includes Kwagga Smith (30) and Marco van Staden (28), while Marvin Orie (30) partners Kleyn at lock.
Props Vincent Koch (33) and Ox Nche (28) pack down either side of Mbonambi in the front row, while versatile Deon Fourie (36) is on the bench to cover both hooker and loose-forward.
"We have been rotating and testing players in different positions since last season to put us in the fortunate position to have a group of 33 players in France that are closely matched in terms of their quality of play and skills,” Nienaber said.
"(They) have been pushing one another for places in the last few months. It has allowed us to select a top-quality team for this match.”
