South Africa had slumped to 40 for three in their second innings at lunch on the fourth day, with the Proteas needing a further 340 runs to reach an imposing victory target of 380.
Hashim Amla was 11 not out after Temba Bavuma (12) fell to the last ball before lunch in a match South Africa needed to win if they were to end a four-match series all square at 2-2.
South Africa have not lost a Test series in England since 1998 and in their past 19 away Test series they have suffered just one campaign reverse -- against India in 2015/16.
The most yet made by any side to win in the fourth innings of a Test at Old Trafford is England's 294 for four against New Zealand in 2008.
South Africa's already difficult task was not helped when, after rain briefly delayed the start of their chase, they slumped to 18 for two.
Dean Elgar, who made a gritty second-innings hundred in England's 239-run victory in the third Test at The Oval, fell for five on Monday when caught behind off Stuart Broad.
Yet again this series, Bavuma walked out to bat with South Africa in trouble.
The experienced Amla battled away, taking 40 balls to score his first boundary when he whipped off-spinner Moeen Ali for four.
But on the stroke of lunch, Bavuma was caught behind off Toby Roland-Jones, although England had to review umpire Kumar Dharmasena's original not out decision to confirm a thin nick.
Earlier, England were bowled out for 243 in their second innings after resuming on 224 for eight.
Morne Morkel wrapped up the innings by dismissing tailenders Broad and Anderson during a spell of two wickets for one run in four balls.
The tall fast bowler finished with fine figures of four for 41 in 13.1 overs.
But Ali's 66-ball innings, including nine fours and three sixes, maintained England's grip on this match.
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