The Proteas bowled out the home side for 161 before lunch on the fourth day, rattling through their last eight wickets for 32 in 116 balls, after routing Australia for 85 in the first innings.
The overpowering victory followed a 177-run win against Steve Smith's shattered team in the first Perth Test, with South Africa emulating the intimidating West Indies sides of the 1980-1990s with three straight series wins in Australia.
"I didn't expect it to happen that quickly, to get eight wickets in one of those sessions and one we will always remember as a team that won us a series," victorious skipper Faf du Plessis said. "That ranks right up at the top.
"It is special for us. To win a series 2-0 with one game to play, I am very proud of the way the team is moving forward."
The second innings destruction cranked up more pressure on Australian skipper Smith and coach Darren Lehmann and intensified calls for significant team changes for the final day-night Test in Adelaide next week.
It was Australia's fifth consecutive Test defeat this year, having also lost all three Tests in Sri Lanka in August.
'Something has to change'
"It is not working. Obviously on the back of five losses there is going to be a lot talked about in regards to selection and things like that," Smith said.
"We?ve got to start finding a way to turn things around. Whether the ball is seaming or spinning or swinging we don?t have an answer at the moment.
"We are not resilient enough, we are not digging in enough, we are not having the pride in our wicket ...something has got to change."
The Australians fell apart again on Tuesday, losing their last eight wickets with all the apparent weaknesses painfully exposed by potent South African pace bowling.
Kyle Abbott and Kagiso Rabada led the rampage with Abbott taking six for 77 and young gun Rabada four for 34.
Once Usman Khawaja was out just 20 minutes into the fourth day, the wickets continued to tumble.
Khawaja was twice beaten by Abbott's movement off the pitch before he went for a cut on the last ball of the over and nicked to wicketkeeper Quinton de Kock for 64.
It was a body blow for Australian hopes of salvaging a Test which was effectively on day three after Sunday's play was entirely washed out, and ended a 50-run stand with Smith.
It brought Adam Voges to the crease under immense pressure to save his faltering Test career after a highest score of 47 in his last 10 innings.
But Voges' self-doubt showed when he tried to withdraw from an attempted pull shot only to glide a deflection to JP Duminy in the gully for two after scoring a duck in the first innings.
Callum Ferguson was the victim of another ugly dismissal, bending to evade Rabada only to glove to Dean Elgar at third slip for one after scoring three in the first innings of his debut Test.
Wicketkeeper Peter Nevill was the next to go, failing to avoid a Rabada bouncer and gloving to Duminy in the gully for six, while Joe Mennie lasted just two balls before he was leg before to Rabada.
The Proteas claimed Smith's prized wicket, caught behind off the rampaging Rabada for 31, after his defiant unbeaten 48 in the first innings shambles.
Mitchell Starc came to the crease but became Abbott's fifth victim, caught behind for a duck, with Nathan Lyon the last man out, giving man-of-the-match Abbott his sixth dismissal.