Skipper Jonny Wilkinson inspired England to a shock 19-17 interval lead, kicking 14 points and converting Saracens wing Dan Scarbrough's interception try.
But Wilkinson could add just three further points after the break as South Africa underlined their credentials as powerful World Cup contenders later this year by running riot.
Brilliant wing Bryan Habana claimed two tries - his second a stunning solo effort - while there were also touchdowns for number eight Pierre Spies (2), scrum-half Ricky Januarie, lock Bakkies Botha, flanker Schalk Burger and full-back Percy Montgomery.
Former Newport star Montgomery finished with 18 points, and fly-half Butch James slotted the final conversion, leaving England out on their feet following a record 58-10 drubbing in Bloemfontein last Saturday.
In two games, England have conceded 113 points and 15 tries to the Springboks, although given the numerous players the tourists did not have at their disposal, it still means little ahead of this September's pivotal World Cup pool clash in Paris.
South Africa were too strong, too ruthless and too quick, leaving England to reflect on few positives from a forgettable trip.
Hooker Mark Regan, prop Kevin Yates and centre Mathew Tait all pressed World Cup claims, but the sooner head coach Brian Ashton can forget about this fruitless mission and build towards a World Cup training camp later this month, the better.
England, hoping for a confident start, blundered from the kick-off when flanker Nick Easter spilled possession and Roy Winters drifted offside to give South Africa an immediate scoring chance, but Percy Montgomery's penalty fell short.
England did not learn their lesson, and when French referee Joel Jutge awarded the Springboks a second penalty on four minutes, Montgomery made no mistake from 45 metres.
But the game's first scrum ended in a penalty for the visitors that Wilkinson arrowed between the posts, making it 3-3 after nine minutes.
England were determined to make a mark, and Easter duly delivered, smashing Springboks flanker Juan Smith in a tackle that forced the bloodied openside off for treatment, meaning an early opportunity for his replacement Bobby Skinstad.
England had a chance to go ahead on 18 minutes, but although Wilkinson scuffed a 48-metre penalty, the visitors took considerable comfort from a promising opening quarter when they gave as good as they got.
But that impressive work was undone in the 23rd minute through an opportunist Springboks try.
Scrum-half Januarie kicked deep into England's 22, and with Montgomery chasing, the ball bounced wickedly over Noon's head and Januarie gathered to touch down. Montgomery converted, hoisting South Africa 10-3 clear.
Wilkinson slotted a second penalty after Scarbrough and Montgomery both required treatment following a crunching midfield collision, and England continued to show composure, thwarting South African attempts at swinging possession wide.
Akona Ndungane was a threat on the right wing though, and only Brown's despairing tackle prevented a try, but from the ensuing scrum, England's defence was buckled as lock Victor Matfield drove Burger over for South Africa's second touchdown, again converted by Montgomery.
As in Bloemfontein, England were punished in ruthless fashion after a promising start, but Wilkinson at least completed his penalty hat-trick as half-time approached.
And then Wilkinson kicked a fourth penalty after Habana was sin-binned for a deliberate knock-on when Brown tried to free Easter, and England incredibly struck another blow.
In the half's final move, Spies threw out a pass intercepted by Scarbrough, who sprinted clear to score. Wilkinson's conversion, astonishingly, meant England led 19-17 at half-time.
South Africa could scarcely believe England's impudence, and they must have received a vociferous half-time lecture from coach Jake White.
And it looked to have worked when they claimed a try within four minutes of the restart. England's defence was stretched in all directions, before Botha crashed over unmarked on the right wing.
Burger was warned by referee Jutge for a shoulder charge on Skirving - he was fortunate to escape a yellow card - and Wilkinson kicked his fifth penalty, levelling the game.
It was a truly heroic effort by England, who had travelled to South Africa without players from Leicester, Wasps or Bath, and then seen their preparations for both Tests ravaged by injuries and a stomach virus.
The Springboks though were in no mood to be on the receiving end of a shock defeat, and Spies atoned for his earlier error by rampaging through the attempted tackles of Andy Gomarsall, Wilkinson, Noon and Magnus Lund to edge South Africa back in front.
Montgomery again converted, and before England could recover, debutant Skirving's pass was intercepted by Habana, who sprinted 80 metres to score, with Montgomery converting and putting South Africa out of sight at 36-22 ahead.
The tourists were forced into a prolonged rearguard action, having conceded almost a point a minute in the second period, but South Africa had every intention of increasing their tally.
With 15 minutes remaining, Montgomery scored South Africa's sixth try, slicing through weary England cover. His conversion made it 43-22, leaving England desperately counting down the clock to try and avoid further punishment.
Habana conjured a scintillating score that left England's defence floundering and took South Africa to within sight of a half-century. Spies then brought up the 50 points with South Africa's eighth try, which was converted by James.