It proved an emphatic triumph for South Africa's bowling attack, who nullified the threat of England's new attacking batting 'Bazball' approach, forging a 161-run first innings lead before dismissing their hosts in only 37.4 second innings overs.
Anrich Nortje took three wickets in the space of 10 balls to rip through the heart of the home batting, removing Jonny Bairstow (18 runs), opener Alex Lees (35) and Ben Foukes (0) in quick succession with a spell of fast bowling for figures of 3-47.
He was ably backed up by fellow quicks Marco Jansen, Lungi Ngidi and Kagiso Rabada while spinner Keshav Maharaj proved a surprisingly successfully early inclusion into the attack, taking the first two wickets before lunch with Zak Crawley (13) and Ollie Pope (5) both trapped leg before wicket.
It was another failure for under-pressure Crawley, who was the first to fall for 13 runs and faces being dropped for the next test at Old Trafford.
His future in the England team has been under a cloud for a while and an average of 22.25 after 35 innings as a test opener will have the selectors reconsidering his place in the team ahead of the next two tests in the series.
Joe Root was the first to go after lunch as he edged Ngidi to slip for six runs followed by Nortje’s quick trio of scalps as South Africa took a firm grip on the game.
But England captain Ben Stokes and Stuart Broad took on the bowlers in a ‘Bazball’ cameo to score 55 runs off 45 runs for the seventh wicket to offer hopes of a home fightback before Broad was snagged by Rabada for a quickfire 35.
Jansen then castled Matthew Potts for a single run before Stokes (20) hit Rabada down the throat of Maharaj on the boundary to end any slim hopes for the hosts.
Rabada's seven wickets in the test - including a 5-fer in the first innings - saw him named man of the match.
Captain Dean Elgar said the bowlers had to put the ball in the right areas and "the guys did a great job".
"It was disappointing to lose but South Africa were just better than us, but I don't want to look too much into it," added Stokes.
South Africa had begun the day on 289-7 in response to England's first innings tally of 165 and batted for the first hour on Friday before being bowled out for 326 in their first innings, giving them a handy 161-run lead.
Nortje scored an unbeaten 28 not out off 42 balls as he dominated a 29-run partnership for the ninth wicket with Marco Jansen, who was dismissed for 48.
Rabada was out third ball of the day as he pulled the ball leg side, only for Broad to pluck it one-handed out of the air for a brilliant catch.