With the game taking place outside World Rugby's official window for Test matches, the world champions will be without Cheslin Kolbe (wing), Andre Esterhuizen (centre), Cobus Reinach (scrum-half), Jasper Wiese (No. 8) and Vincent Koch (prop), who have all returned to their respective English and French clubs.
Nienaber had made six changes to the starting XV that thrashed Italy 63-21 in Genoa last weekend, with Makazole Mapimpi (wing), one of the try-scoring heroes of their 2019 World Cup final win over England in Japan, recalled.
Jesse Kriel is in at centre, while Evan Roos (No. 8) and Eben Etzebeth are back in the pack.
The Springboks have also made two positional switches, with Kurt-Lee Arendse on the right wing after playing on the left in Genoa and Damian de Allende moving from outside centre to inside centre to partner Kriel.
There are also four changes on a replacements bench featuring a split of five forwards and three backs, with SA 'A' captain Thomas du Toit (prop), Marco van Staden (flanker), Jaden Hendrikse (scrum-half) and Canan Moodie being drafted in.
"With this Test falling outside the international Test window, we knew we would have to make changes to the team, but we are pleased with the depth we have built in the wider squad in the last few months, and it is paying off for us this week," said Nienaber.
"Every player in this squad has played Test rugby. It doesn't get bigger than playing against England at a packed Twickenham in the last Test of the season for a player, and one can sense the excitement among the players about this occasion."
Before the Italy match, South Africa had suffered narrow Autumn defeats by both Ireland (19-16) and 2023 World Cup hosts France (30-26).
'Epic encounter'
England, who came from 19 points down to snatch a dramatic 25-25 draw with New Zealand at Twickenham last weekend, are due to name their team on Thursday.
The astonishing fightback against the All Blacks came after England launched their November campaign with a narrow 30-29 loss at home to Argentina before they overwhelmed Japan 52-13.
"England will enter this match with the same mindset as us - to finish the season on a high note after a tough November campaign, and to build momentum with an eye on the World Cup," said Nienaber.
"So, we are expecting them to throw everything they have at us. They are a well-balanced team with a strong pack of forwards and exciting backs, and they are well-coached, so we know it is going to be an epic encounter.
"We lost against them by one point in our last two matches at Twickenham and the last time we beat them in London was in 2014, so we have to be accurate in all areas of our game, effective in our execution and we need to convert our chances into points.
"We had two narrow defeats against the top two teams in the world in Ireland and France and we defeated Italy, and it would be fantastic if we could finish the tour on a high note."
This match will also see Springboks director of rugby Rassie Erasmus complete a two-game matchday ban imposed by World Rugby for his criticism of referees following the Ireland and France matches.
South Africa (15-1)
Willie le Roux; Kurt-Lee Arendse, Jesse Kriel, Damian de Allende, Makazole Mapimpi; Damian Willemse, Faf de Klerk; Evan Roos, Franco Mostert, Siya Kolisi (capt); Marvin Orie, Eben Etzebeth; Frans Malherbe, Bongi Mbonambi, Ox Nche
Replacements: Malcolm Marx, Steven Kitshoff, Thomas du Toit, Marco van Staden, Kwagga Smith, Jaden Hendrikse, Manie Libbok, Canan Moodie
Coach: Jacques Nienaber (RSA)
