Joe Launchbury will start his first Test, Tom Wood takes over from Tom Johnson while Alex Corbisiero comes in for Joe Marler at loosehead prop.
Mike Brown (Harlequins) replaces Charlie Sharples on the left wing and Ben Youngs partners Leicester Tigers' team-mate Toby Flood at halfback.
There are also call-ups to the bench for the first time in this series for James Haskell, Mouritz Botha and Jonathan Joseph.
England Head Coach Stuart Lancaster said:
"We have picked a team that will give us the best chance of beating South Africa. There were some tight calls, which is what you want as coaches, but the players we have brought into start have been training well, will bring a real motivation to make the most of their opportunity and will suit the challenge we face against a tough and physical South African team."
London Wasps lock Tom Palmer is continuing to be treated for a mild calf injury.
England (v South Africa, 2.30pm Saturday, Twickenham Stadium)
15. Alex Goode (Saracens, 4 caps)
14. Chris Ashton (Saracens, 27 caps)
13. Manusamoa Tuilagi (Leicester Tigers, 15 caps)
12. Brad Barritt (Saracens, 9 caps)
11. Mike Brown (Harlequins, 9 caps)
10. Toby Flood (Leicester Tigers, 52 caps)
9. Ben Youngs (Leicester Tigers, 26 caps)
1. Alex Corbisiero (London Irish, 16 caps)
2. Tom Youngs (Leicester Tigers, 2 cap)
3. Dan Cole (Leicester Tigers, 33 caps)
4. Joe Launchbury (London Wasps, 2 caps)
5. Geoff Parling (Leicester Tigers, 10 caps)
6. Tom Wood (Northampton Saints, 11 caps)
7. Chris Robshaw (Harlequins, capt, 10 caps)
8. Ben Morgan (Gloucester Rugby, 7 caps)
16. David Paice (London Irish, 4 caps)
17. David Wilson (Bath Rugby, 21 caps)
18. Mako Vunipola (Saracens, 2 cap)
19. Mouritz Botha (Saracens, 9 caps)
20 James Haskell (London Wasps, 43 caps)
21. Danny Care (Harlequins, 35 caps)
22. Owen Farrell (Saracens, 10 caps)
23. Jonathan Joseph (London Irish, 3 caps)