With no play possible on day two due to rain, the Proteas resumed their first innings on 171-5, having bowled the Aussies out for 85 on the first morning.
De Kock (104) and Temba Bavuma (74) added a further 105 runs to their unbroken 39-run stand as the tourists - already 1-0 up in the three-match series - took control of the Test.
After South Africa had been dismissed for 326, with a lead of 241 runs, Australia's second innings started miserably when Joe Burns flicked one wide outside leg stump to keeper De Kock.
Steve Smith took over, and he and Khawaja added another 42 before the final interruption to play for bad light.
Australia still trail by 120 ahead of day four, but with eight wickets in hand.