AB de Villiers and debutant JP Duminy stitched a match-winning 111-run fifth-wicket partnership to script the historic win and hand Greame Smith and Co 1-0 lead in the three-match series.
With this win South Africa are inches away from dethroning Australia from the pinnacle of Test cricket. This result comes within days after India successfully chased 387 in the first Test against England in Chennai.
According to a cricket website, De Villiers stood like a rock in his unbeaten 106-run innings which came off 186 balls. Duminy (50) provided him perfect company as the duo went about their business cautiously.
De Villiers frustrated the Australian bowlers as he hit just nine boundaries in his 276-minute stay at the crease, while Dumniy struck four fours and a six in his 119-ball innings.
Earlier resuming at the overnight score of 227 for three, Mithchel Johnson cut short Jacques Kallis (57) innings, when he had him caught by Michael Hussey.
However, De Villiers and Duminy stood tall and ensured the epic victory in just 55.2 overs on the final day.
Duminy scored the winning runs and leapt in air pumping his fist as skipper Graeme Smith, who set the chase with a haughty century (108) erupted with the entire team.
The successful run chase by South Africa is a Test record between the two nations and second only to West Indies's 418-7 against Australia in Antigua in 2002-03.