The tourists were sent in chasing 448 to win as South Africa declared on 270 for five in the second innings.
Chris Rogers on 21 runs and David Warner with 10 to his name were at the crease for Australia at the interval.
Hashim Amla ended unbeaten on 127 after facing 176 balls with JP Duminy on 18 at the other end. Amla brought up his century off 139 balls, his 21st of his career and fifth against Australia, as the South African lead approached 400 in the morning session.
Quinton de Kock was the only South African batsman to depart on the day as he scored 34 runs from 58 deliveries. De Kock was out caught by Michael Clarke off the bowling of Nathan Lyon.
Mitchell Johnson had the best figures for Australia in the innings with 2/51.