Toby Flood is recalled at fly-half to start alongside clubmates Ben Youngs, Manu Tuilagi, Dan Cole and Geoff Parling.
Flood will make his 49th appearance for England in the second Test as the tourists look to bounce back from a 22-17 in last weekend’s opener.
Cole wins his 30th cap in an unchanged forward pack, while Tuilagi moves to inside centre as London Irish’s Jonathan Joseph starts his first international at Coca Cola Park in the number 13 shirt.
England head coach Stuart Lancaster said: “Toby has waited patiently for his opportunity and the time is right to allow him the chance to demonstrate his experience and skills in what will be a very tough challenge.
"To have two 21-year-old centres is exciting and we are looking forward to seeing this combination in action.”
The remaining four Leicester players on the tour – Thomas Waldrom, Graham Kitchener, Anthony Allen and Tom Youngs – played their part in England’s midweek win over South Africa Southern Barbarians on Wednesday afternoon.
England (v South Africa, Coca Cola Park, 4pm BST, live on Sky Sports HD & BBC Radio 5 Live)
15 Ben Foden (Northampton Saints)
14 Chris Ashton (Northampton Saints)
13 Jonathan Joseph (London Irish)
12 Manusamoa Tuilagi (Leicester Tigers)
11 David Strettle (Saracens)
10 Toby Flood (Leicester Tigers)
9 Ben Youngs (Leicester Tigers)
1 Joe Marler (Harlequins)
2 Dylan Hartley (Northampton Saints)
3 Dan Cole (Leicester Tigers)
4 Mouritz Botha (Saracens)
5 Geoff Parling (Leicester Tigers)
6 Tom Johnson (Exeter Chiefs)
7 Chris Robshaw (Harlequins)(c)
8 Ben Morgan (Scarlets)
16 Lee Mears (Bath Rugby)
17 Alex Corbisiero (London Irish)
18 Tom Palmer (Stade Francais)
19 Phil Dowson (Northampton Saints)
20 Lee Dickson (Northampton Saints)
21 Owen Farrell (Saracens)
22 Alex Goode (Saracens)