Australia were 205 for eight at lunch, still 218 runs behind South Africa's first innings total of 423.
South Africa went into lunch in a strong position but dropped two catches and suffered two injuries.
Steve Smith and Brad Haddin both survived chances, while Hashim Amla and Wayne Parnell had to leave the field because of injuries.
Amla suffered a dislocated left ring finger when he got his fingers to a high slash by Haddin, on one, at gully off Vernon Philander. Haddin made only nine before he had his middle stump uprooted by a fast, straight ball from Dale Steyn.
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Having picked just four specialist bowlers, South Africa suffered a blow when Wayne Parnell pulled up with a groin injury midway through his ninth over.
David Warner added just five runs to his overnight 65 before he edged a drive against Philander to Graeme Smith at slip. Nightwatchman Nathan Lyon withstood a battering from fast bowler Morne Morkel before chopping a short ball onto his stumps after making 15 off 43 balls.