England needed four wickets to complete an emphatic triumph and took just 100 minutes to do so.
England won the third Test on Monday but made heavy weather of wrapping up South Africa's tail on the last day at St George's Park to go 2-1 up in the series after a dominant innings and 53-run victory.
England needed four wickets to win in their 500th overseas Test, but had to overcome late resistance and feisty 71 from Keshav Maharaj and 39 from debutant Dane Paterson before completing the task 10 minutes before lunch.
They bowled South Africa out for 237 in their second innings for a commanding victory after forcing the follow-on, when the home side were 209 all out in their first innings in reply to a mammoth 499 for nine declared.
Maharaj and Paterson put on a ground Test record partnership of 99 for the last wicket as they frustrated the England bowlers.
But it was only a matter of time before England completed their first away victory by an innings since success in Sydney in 2011.
"It's a great template for how we want to play our Test cricket with big first innings score and drive it on from there," said England captain Joe Root.
It took just three balls on Monday for England to claim their first victim as Stuart Broad forced Vernon Philander (14) to play an inside edge onto his pad that popped up for Ollie Pope to take his sixth catch of the match.
Mark Wood's first ball after replacing Broad saw him force Kagiso Rabada into a leading-edge which flew up to mid-on where Broad took an easy catch. Rabada, who will miss the last Test because of suspension, scored 16 off 24 balls.
Dom Bess' first over saw him skid a ball on to bowl Anrich Nortje (5), leaving Paterson to join Maharaj for a late cameo that proved the home side's best partnership of poor Test performance.
Maharaj was eventually run out, but not before smashing his way to a second Test 50.
Root bowled 10 successive overs as he went in search for a first Test five-wicket haul, having taken four overnight, but without success.
He even tried his luck with the new ball but Maharaj hit him for three successive fours and then two sixes in an over before the England skipper took himself off.
South Africa won the first Test in Pretoria by 107 runs but England bounced back with a 187-run win in Cape Town in the second test. The final Test in Johannesburg starts on Friday.