England, set a record 346 for victory, were dismissed for 294 after some plucky counter-attacking by Matt Prior [ Images ] (73), Jonny Bairstow (54), Graeme Swann [ Images ] (41) and Stuart Broad [ Images ] (37).
Jonathan Trott also chipped in with 63 and for a time it looked like England could pull of a miracle but ultimately the target was just too high.
The end of the match, and series, was sealed when last man Steven Finn was caught by second slip Jacques Kallis [ Images ] off Vernon Philander, who finished with two wickets in two balls for figures of five for 30.
Philander had also played two vital innings in the match of 61 and 35.
It was always going to be a difficult challenge for England given that West Indies [ Images ] are the only team ever to have successfully chased a target beyond 300 at Lord's, when they made 344 for one in 1984. England's highest run chase is 332 for seven against Australia [ Images ] in 1928.
There was some late drama on the last day when Prior and Swann added 74 from just 66 deliveries. The crowd, basking in bright sunshine, began to sense something incredible might be about to happen. But England's lack of wickets in hand cost them.
The defeat meant England surrendered their position at the top of the world rankings after holding the title for a year having displaced India [ Images ].
England have lost six tests in 11, while South Africa remain undefeated in away series for six years.
Too many players under-performed for England with captain Andrew Strauss [ Images ] averaging just 17.83 with a top score of 37 in the three-match series. Top batsmen Kevin Pietersen [ Images ], born in South Africa, was dropped for the deciding test for sending derogatory texts about England to their rivals.
Conversely, South Africa's batsmen prospered with Hashim Amla [ Images ] hitting a national record 311 not out in the first Test at The Oval.
Photograph: Gareth Copley/Getty Images