Thorpe scored 118 not out in England's 570 for seven declared, their third highest second innings total in Test history. Thorpe batted for more than five hours, facing 209 balls and hitting 15 fours.
South Africa, who are chasing a target of 378, were 21 for one at the close. Herschelle Gibbs was 11 not out with nightwatchman Nicky Boje on four after Matthew Hoggard trapped captain Graeme Smith lbw for five.
South Africa scored 332 in their first innings in reply to England's 139.
The difference of 431 runs between England's two innings was their biggest disparity in Test history, surpassing the difference of 400 runs when Australia dismissed England for 75 and 475 in Melbourne in 1894-95.
England, who won the first Test by seven wickets, resumed on 281 for one but in the fifth over of the day Andrew Strauss edged fast bowler Makhaya Ntini to Martin van Jaarsveld at third slip.
Strauss scored 136 in more than six hours at the crease in which he faced 285 balls and hit 16 fours.
Eight overs later Ntini struck again to have Michael Vaughan caught behind down the leg side by wicketkeeper AB de Villiers for 10.
FLOWING SHOTS
England were 314 for four within five overs when Mark Butcher, on 13, edged Jacques Kallis again to Van Jaarsveld in the slips.
Geraint Jones joined Thorpe to add 132 runs for the sixth wicket in another aggressive stand.
South Africa employed a long stop for the final overs of the innings in an attempt to stem the flow of runs.
Jones smashed 73 off 82 balls including two sixes in a frenetic innings before lofting a drive off left-arm spinner Nicky Boje to Ntini on the long-on boundary.
The declaration came when fast bowler Dale Steyn had Ashley Giles caught behind by De Villiers for nought.
Ntini finished with two for 111 from 37 overs and Boje toiled for 44 overs for his figures of one for 163.
South Africa had an escape in the fourth over of their innings when wicketkeeper Jones failed to hold on to a thick edge from Gibbs off Steve Harmison with the opener on six.
Scorecard:
England first innings 139
South Africa first innings 332 (J.Kallis 162)
England second innings (overnight 281-1)
M.Trescothick c de Villiers b Pollock 132
A.Strauss c van Jaarsveld b Ntini 136
M.Butcher c Van Jaarsveld b Kallis 13
M.Vaughan c De Villiers b Ntini 10
G.Thorpe not out 118
A.Flintoff c De Villiers b Smith 60
G.Jones c Ntini b Boje 73
A.Giles c De Villiers b Steyn 0
Extras (b-3 lb-8 nb-15 w-2) 28
Total (for seven wickets decl, 172.3 overs) 570
Did not bat: M Hoggard, S Jones, S Harmison
Fall of wickets: 1-273, 2-293, 3-306, 4-314, 5-428, 6-560, 7-570
Bowling: Pollock 36-16-79-1 (nb-3), Ntini 37-4-111-2 (nb-3 w-2), Steyn 25.3-2-122-1 (nb-9), Boje 44-5-163-1, Kallis 25-4-57-1, Smith 5-1-27-1
South Africa second innings
G.Smith lbw b Hoggard 5
H.Gibbs not out 11
N.Boje not out 4
Extras (lb-1) 1
Total (for 1 wicket, 9 overs) 21
Fall of wicket: 1-12
To bat: J.Rudolph, J.Kallis, M.van Jaarsveld, H.Amla, A.de Villiers, S.Pollock, M.Ntini, D.Steyn.
Bowling: Hoggard 5-0-17-1, Harmison 4-1-3-0
