The Proteas' pacemen triggered an Australian batting collapse which saw the tourists finish day two a whopping 378 runs behind with four wickets in hand.
Even the follow-on could factor in as a final insult for a reshuffled Australian side in a damaging tour, after Temba Bavuma's unbeaten 95 helped South Africa to a mammoth first innings 488 all out.
Bavuma ran out of partners to be stranded on 95, five runs short of a second Test ton, but it was an innings of first graft then style as he received a standing ovation for his efforts.
In response, Australia looked crippled at 6-110, with only Usman Khawaja (53) offering genuine resistence to the hosts' pace and spin attack.
At stumps, Tim Paine was 5 not out alongside Pat Cummins, unbeaten on 7, but the task to save the match, weather aside, looks grim.
The new opening pair of Matt Renshaw (8) and Joe Burns (4) did not last long, while Peter Handscomb — preferred in the line-up to 12th man Glenn Maxwell — chopped onto his stumps for a first-ball duck.
Shaun Marsh (16) and Mitchell Marsh (4) fell in quick succession as six wickets fell for 96, with the tourists still 178 runs short of avoiding the follow-on.
Look back at how day two unfolded in our live blog.
