Vernon Philander took five wickets as South Africa replaced England as the world's No.1 Test side with a 51-run win in the third Test at Lord's on Monday.
Set 346 for victory, England were dismissed for 294 on Monday's final day as South Africa took the three-match series 2-0.
Man-of-the-match Philander wrapped up the contest with two wickets in two balls to finish with 5-30 after Matt Prior had threatened to lead England to an improbable victory with a dashing 73.
This was England's first home series defeat since losing to South Africa four years ago and the first time they'd lost two or more Tests in a home campaign since the 2001 Ashes.
"That was a bit closer than we were hoping, Prior and (Graeme) Swann played some incredible shots after tea so we had to hang in there, as we knew the new ball was around the corner," said South Africa captain Graeme Smith.
"Vernon Philander was outstanding with bat and ball."
England captain Andrew Strauss added: "We're all bitterly disappointed."
South Africa, who won the first Test at The Oval by an innings and 12 runs before the second Test at a draw at Headingley, only had to avoid defeat at Lord's to replace England at the top of the International Cricket Council's world Test rankings.
History was against England as the most they had ever made in the fourth innings to win a Test was the 7-332 they posted against Australia at Melbourne back in 1928/29.
Seam bowler Philander had removed Strauss, in his 100th Test, and fellow left-handed opener Alastair Cook on Sunday to reduce the hosts to 2-16 at the fourth day's close.
Philander struck again early Monday when he had Ian Bell caught, at the second attempt, for his overnight score of four by Smith at first slip before a terrible mix-up saw James Taylor run out.
Jonathan Bairstow, who made a gallant 95 after coming in at 4-54 in the first innings having replaced the dropped Kevin Pietersen, walked out to bat Monday with England in an even worse position at 4-45.
But he showed his class before playing back to a low delivery from leg-spinner Imran Tahir to be bowled for 54 off just 47 balls with eight fours.
And 5-134 became 6-146 when Jonathan Trott was brilliantly caught by second slip Jacques Kallis off fast bowler Dale Steyn for 63 after more than three-and-a-half hours at the crease.
Left-handed batsman Stuart Broad pulled Steyn for six but a stand of 62 with Prior ended when, on 37, he hooked a Kallis bouncer to Amla at long leg.
At tea, England were 7-221, still needing a further 125 runs for victory.
England then scored rapidly with Swann driving leg-spinner Imran Tahir and hooking fast bowler Kallis for two impressive sixes.
Prior meanwhile had gone to his own fifty in 107 balls with five fours and he made sure the attack continued by sweeping Tahir to the boundary.
A run out derailed England's charge, Tahir gathering Jacques Rudolph's wild throw to leave Swann, whose 41 also featured five fours, short of his ground.
Together with Prior, he'd put on 74 in 66 balls but England were now 8-282.
Prior, on 67, was reprieved when he holed out to JP Duminy off Morne Morkel only for replays to indicate a no-ball.
But on 73 he edged Philander, armed with the new ball to Smith and next ball the all-rounder, who also made valuable runs, had last man Steven Finn caught by Kallis.