Craig Matthews and Brian McMillan took three wickets apiece, as England, given a target of 456 when South Africa declared at lunch, could only manage 99 runs Sunday.
It was another low in a humiliating two-year spell for the country that invented the game. Never before had England been bowled out for less than 100 at Lord's. Its previous lowest score for an innings at the hallowed ground was 116 against Australia in 1972.
The victory was South Africa's first at Lord's in 59 years, and sealed once and for all the end of the country's international cricket isolation imposed because of apartheid.
South Africa has yet to lose a Test series since it was readmitted to Test cricket two years ago, and can clinch its first series in England since 1965 with just one victory in the last two Tests.
On the field, McMillan and Matthews starred with the bat as well as the ball, pushing South Africa's second innings score to an unassailable tally.
South Africa had resumed on 195 for four, but England's fast bowler Darren Gough took three wickets in the morning session with beautifully controlled inswing with the old ball.
Gough took the wickets of Jonty Rhodes and Peter Kirsten in the same over with similar inswinging yorkers that knocked over the middle stump.
Rhodes made his second 32 for the match to make the score the 208 for five, and one run later Kirsten was gone, having added only four to his overnight 40 not out.
With the score on 220, Angus Fraser swung one away from David Richardson, who took an edge which keeper Stephen Rhodes took well behind the wicket moving to his right.
McMillan and Matthews stopped the bleeding with a 58-run stand, McMillan finishing on 39 not out and Matthews bowled for 25 by another inswinger from Gough in the last over before lunch.
Gough had figures of four for 46, and finished with eight wickets for the match.
Set an improbable target, England's went to bat with a draw as its only hope, but even that goal evaporated when three wickets were gone before tea.
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