After Sunday's second day was washed out, the Australians were hunting for early wickets to put a brake on the Proteas after they were routed for a record low total of 85 on Saturday.
But de Kock and Temba Bavuma batted South Africa into a position of strength with a century stand for the sixth wicket and a 203-run lead to put even more pressure on Steve Smith's embattled team.
His stand of 144 with Temba Bavuma was the highest by a visiting team in Hobart for the sixth wicket.
At lunch, the Proteas were 288 for six with Bavuma unbeaten on 74 and Vernon Philander on three.
De Kock became only the fourth South African to register 50 or more in five consecutive Tests after he swept spinner Nathan Lyon for four over wide mid-on.
He has proved a thorn for Australia in this series following scores of 84 and 64 in the first Test victory in Perth.
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