The world champions, who had not lost to England for four years, rarely looked in danger of losing that proud record as they ran in tries from flanker Willem Alberts and wing Lwazi Mvovo to win a bruising contest.
Flyhalf Morne Steyn added three penalties and a conversion, with England's points coming from two first-half penalties from Toby Flood and a late interception try from Ben Foden.
Victory was no less than South Africa deserved after a ferociously committed effort that left England bruised and battered. Both flanker Tom Croft and flyhalf Flood departed injured long before the final whistle.
The defeat came as a setback to England manager Martin Johnson, who had seen his young team notch victories over Australia and Samoa in the past fortnight following an earlier defeat by New Zealand.
Flood had kicked England into a 3-0 lead on six minutes, after a sweeping English counter-attack featuring a gallop down the touchline from Croft forced South Africa onto the back foot.
Ben Youngs was shoulder-charged late by prop Jannie Du Plessis, leaving referee George Clancy no option but to whistle for the penalty.
But with South Africa exerting fearsome pressure on England at the scrum, it was only a matter of time before the Springboks drew level.
England had conceded two free-kicks within the opening 10 minutes and Clancy lost patience at another collapse on Andrew Sheridan's side in the 11th minute, leaving Morne Steyn to kick South Africa level.
Flood made it 6-3 midway through the half after South Africa were whistled for not moving away but from the ensuing kick-off England suicidally elected to run from deep in their own 22, ultimately conceding a five-metre scrum.
England nearly paid the price and had Youngs to thank for a desperate challenge on Matfield that denied the Springbok captain a certain try.
Croft meanwhile became the first casualty shortly afterwards, leaving the field with what looked like a shoulder injury, crucially diminishing England's line-out options.
South Africa saw two more penalty attempts hit the posts - one a routine effort from Morne Steyn, the other a long-range from Frans Steyn - and were denied a try after a cover tackle by Foden on Springbok No.8 Pierre Spies.
England suffered another key injury shortly afterwards, Flood coming off and replaced by Charlie Hodgson.
Yet South Africa's relentless pressure finally told on 35 minutes when Morne Steyn punished England lock Tom Palmer for coming in on the wrong side of a ruck, leaving Steyn to slot the three points.
Moments later the South Africa flyhalf missed a drop goal attempt from in front of the posts and England were relieved to turn round level.
Another Steyn penalty on 43 minutes left England 9-6 down, and despite a frenzied English assault on the South African line, including one 19-phase attack, the world champions defence held firm.
Instead it was South Africa who seized the initiative next, when, after an attacking line-out deep in the English 22, the ball was recycled and spun wide to replacement flanker Willem Alberts, who dotted down in the corner to give South Africa a 14-6 lead heading into the final quarter.
With wave after wave of English attacks foundering on South Africa's defence, the game was sealed 10 minutes from time, when Mvovo burst through a non-existent tackle from England wing Chris Ashton to score.
Steyn converted for 21-6 and although England hit back with a late interception try from Foden, centre Mike Tindall missed a drop-kick conversion from in front of the posts.
Teams
England (15-1)Ben Foden; Chris
Ashton, Mike Tindall, Shontayne Hape, Mark Cueto; Toby Flood, Ben
Youngs; Nick Easter (capt), Lewis Moody, Tom Croft; Tom Palmer, Courtney
Lawes; Dan Cole, Dylan Hartley, Andrew SheridanReplacements: Steve Thompson, Matt Banahan, Danny Care, Hendre Fourie, David Wilson, Simon Shaw, Charlie HodgsonSouth Africa (15-1)Zane
Kirchner; Gio Aplon, Frans Steyn, Jean de Villiers, Lwazi Mvovo; Morne
Steyn, Ruan Pienaar; Pierre Spies, Juan Smith, Deon Stegmann; Victor
Matfield (capt), Bakkies Botha; Jannie du Plessis, Bismarck du Plessis,
Tendai MtawariraReplacements: Adrian Strauss, CJ van der Linde,
Flip van der Merwe, Willem Alberts, Francois Hougaard, Patrick Lambie,
Adi JacobsReferee: George Clancy (IRL)
http://www.sport24.co.za/Rugby/BoksOnTour/Boks-victorious-in-Twickenham-20101127