Leicester Tigers fly-half Flood, 26, made his England debut in November 2006 and has played in the last two World Cup campaigns.
Back-rower Waldrom, 29, made his Test debut as a second-half replacement in last weekend’s second Test following a man-of-the-match display in the midweek win over South Africa Southern Barbarians.
Leicester colleagues Dan Cole, Geoff Parling and Manu Tuilagi retain their places in the starting line-up, though scrum-half Ben Youngs has returned to England after suffering a shoulder injury during his two-try performance in the second Test.
Saracens full-back Alex Goode makes his first international start as Ben Foden moves to the wing.
The other changes see recalls for Danny Care, Alex Corbisiero and Tom Palmer, while James Haskell replaces the injured Chris Robshaw and Waldrom is in for Ben Morgan at No 8. Brad Barritt has recovered from eye surgery and is among the replacements.
England (v South Africa, Nelson Mandela Bay Stadium, 1600 BST, live on Sky Sports HD & Radio 5 Live)
15 Alex Goode (Saracens)
14 Chris Ashton (Northampton Saints)
13 Jonathan Joseph (London Irish)
12 Manusamoa Tuilagi (Leicester Tigers)
11 Ben Foden (Northampton Saints)
10 Toby Flood (Leicester Tigers)
9 Danny Care (Harlequins)
1 Alex Corbisiero (London Irish)
2 Dylan Hartley (Northampton Saints)(c)
3 Dan Cole (Leicester Tigers)
4 Tom Palmer (Stade Francais)
5 Geoff Parling (Leicester Tigers)
6 Tom Johnson (Exeter Chiefs)
7 James Haskell (Highlanders)
8 Thomas Waldrom (Leicester Tigers)
Replacements
16 Lee Mears (Bath Rugby)
17 Joe Marler (Harlequins)
18 Mouritz Botha (Saracens)
19 Phil Dowson (Northampton Saints)
20 Lee Dickson (Northampton Saints)
21 Owen Farrell (Saracens)
22 Brad Barritt (Saracens)
