Australia declared their second innings on 314-6 on the stroke of the tea interval, and the Proteas once again lost Ryan Rickelton early, caught off a short ball from Josh Hazlewood for just 2.
Aiden Markram and David Bedingham then stitched together an 84-run partnership for the second wicket, with both batters looking set just as they did in the first innings.
Hazlewood, however, broke the stand when coming back for his second spell as the seamer trapped Bedingham plumb lbw as the number 3 walked back to the dressing room for 46.
It went from bad to worse for the reigning World Test Champions when captain Temba Bavuma was out, caught at short-leg, off the part-time spin of Matt Renshaw who claimed his maiden Test wicket.
Renshaw would want to put the Kingsmead pitch in his back pocket and play on it every day, having already contributed a career-best 190 in the first innings and then 82 second time around.
Australia then struck one final blow late on the fourth day when skipper Pat Cummins had Tristan Stubbs caught behind, needlessly chasing a full, wide delivery outside his off stump.
Markram was still at the crease and will resume on the fifth morning on 45, with Wiaan Mulder at the other end on 5 and the Proteas still requiring an unlikely 319 for victory.
Australia had resumed on the fourth morning on 33 without loss looking to build on their 106-run lead on the first innings, but lost Travis Head (11) early when the opener was caught at mid-off off left-arm paceman Marco Jansen.
Nic Maddinson, who was under pressure following a 33-ball duck in the first innings, came out attacking and struck six fours and two sixes before being clean-bowled by Anrich Nortje for 48.
The tourists kept their attacking intent as they looked for quick runs before the declaration, with Marnus Labuschagne (37) and Steve Smith (27) both getting starts.
Renshaw went past fifty for the second time in the match, Alex Carey contributed 24 before Beau Webster (39 not out) and Cummins (32 not out) took the lead beyond 400.
Temba Bavuma suffered his first defeat as Test captain after the Proteas went down by 214 runs against Australia in Durban, and the home skipper could not hide his disappointment.
Aiden Markram battled for almost six hours at the crease but a career-best bowling effort from Josh Hazlewood saw Australia complete a 214-run win against the Proteas in the first Test in Durban.
Australia have earned a 139-run lead over South Africa after bowling out the lacklustre hosts for 284 runs in their first innings at Kingsmead Stadium on Sunday.
Australia will welcome Josh Inglis back into their squad ahead of the second Test against South Africa as the wicketkeeper-batter continues his recovery from a fractured finger.
