The tourists produced a blistering display of strokeplay after tea to close on 230-2 – a lead of 292 - in their second innings after bowling Australia out for 163.
Hashim Amla (99 not out) just missed out on a century in a session while Graeme Smith hit 84 in a second-wicket partnership of 178 off just 153 balls.
Australia’s much-changed pace attack laboured under the onslaught as the pair struck 23 boundaries between them.
Nathan Lyon took a fine diving catch at midwicket to dismiss Smith but then dropped a far easier chance to remove Jacques Kallis (17 not out) at cover when the right-hander was on three.
Dale Steyn (4-40) had earlier begun a devastating spell with two wickets in his first over - David Warner (13) caught behind and nightwatchman Nathan Lyon (7) taken in the gully.
Vernon Philander (2-55) soon trapped Ricky Ponting (4), in his final Test, lbw following a review from the batsman. When Michael Clarke (5) nicked a probing Steyn to wicketkeeper De Villiers the home side were in disarray at 45-6.
Matthew Wade (68), helped in particular by debutant John Hastings (32) inspired a fightback but spinner Robin Peterson (3-44) ran through the last three wickets to give his side a crucial first innings lead of 62.
