South Africa were bowled out for 215 in their second innings shortly after tea on day three, despite the best efforts of Delmi Tucker (64 off 181 balls), Chloe Tryon (64 off 153 balls) and Tazmin Brits (31 off 127 balls).
Australia were in an unlosable position after amassing a women's world-record 9(dec)-575 in response to the tourists' measly 76.
But the Proteas made Australia fight hard to wrap up victory on Saturday, with their determination frustrating the home side in the 37-degree heat.
Australia's Test win follows on from 2-1 victories in the ODI and T20 series.
South Africa were always going to be up against it in the first women's Test match between the two nations after losing star allrounder Marizanne Kapp to illness before the match.
The Proteas rocked up on day three in all sorts of trouble at 3-67 in their second dig, but Brits was the only wicket to fall during the morning session.
Ellyse Perry's seaming delivery caught the edge of Brits' bat and the ball flew low to second slip.
Phoebe Litchfield did well to snaffle the catch, but the umpire wasn't convinced it had carried and decided to launch a review.
The end of a 96-run partnership for the Proteas with Phoebe Litchfield holding the catch — cricket.com.au (@cricketcomau) #AUSvSA pic.twitter.com/kHqVzDdLytFebruary 17, 2024
Replays were somewhat blurry, but they seemed to indicate Litchfield had just got her fingers under the ball in time.
Comeback kid Sophie Molineux almost snared a wicket just before lunch, but wicketkeeper Alyssa Healy couldn't hang on to an inside edge from Tryon.
Tryon was given another life on 38 when she was dropped by Beth Mooney at slip.
Spinner Ashleigh Gardner (2-29) took a diving catch off her own bowling to end Tucker's stand, and two overs later she had Nadine de Klerk caught for a duck.
The impressive Darcie Brown (2-47) made the most of the new ball by bowling Sinalo Jafta (nine), and it was Annabel Sutherland who got the key breakthrough when she bowled Tryon.
It's Sutherland's match! — cricket.com.au (@cricketcomau) #AUSvSA pic.twitter.com/M1aPcRmVJjFebruary 17, 2024
Sutherland popped up again to dismiss Nonkululeko Mlaba (15), and spinner Alana King wrapped up the innings.
Sutherland finished with 2-11.
It continued a standout match from the 22-year-old, who posted the fourth-highest score in women's Test cricket on Friday when she blasted 210 off 256 deliveries.
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