England's gritty resistance met a hasty downfall as Anrich Nortje and Kagiso Rabada combined to dismantle the visitors' hopes of achieving an improbable target.
The Headingley parallels seemed to haunt South Africa for much of the initial half of proceedings on the final day of the first Test at Centurion.
However, Ben Stokes' dismissal soon provided an opening to the rampant Proteas quicks, who wrapped up the Test match before the tea break.
South Africa claimed victory by a significant margin of 107 runs in the end and registered their first set of points in the World Test Championship.
The enthralling contest between the two sides seemed neck and neck as opener Rory Burns and top-order batter Joe Denly did well to stave off the threatening spells from Vernon Philander and Rabada in the first hour.
The fifth-day pitch was visibly misbehaving with uneven bounce proving to be a challenge for the tourists.
England made progress at a snail's pace, that eventually resulted in Burns attempting an ambitious pull shot off the bowling of Nortje.
The top-edge landed straight in the hands of the fielder stationed at mid-on and Denly was later removed by Dwaine Pretorius for 31.
England went to lunch with a resolute Joe Root batting alongside Ben Stokes, hero of the miracle win over Australia in Leeds.
South Africa's discipline with the ball started to fade slightly in the post-lunch session as Root pounced on loose deliveries and Stokes gave him sturdy company on the other end.
Just when the momentum began to sway in England's favour, left-arm spinner Keshav Maharaj bowled Stokes to lift his side.
Having attacked Maharaj in the previous over with a couple of meaty blows from the bat fetching him boundaries, Stokes was undone by a sharply turning ball that caught his gloves on the way and clattered the stumps.
An animated roar was unleashed by Maharaj as he was embraced by his celebrating teammates, indicating the importance of the timely breakthrough.
Jonny Bairstow then launched a reckless drive and was caught at gully before Root's fighting vigil at the crease was cut short by Nortje.
The remaining wickets fell cheaply with no substantial contribution from England's much-hyped lower order.
Stuart Broad was the last man to get out as Rabada completed his fourth wicket in the innings.
England were deprived of the chance to become the first team in history to chase down a target in excess of 300 twice in a year.