The Springboks scored five tries to one and dominated territory and possession, with their pack bullying an Australian side which had won their first three Tests under new coach Joe Schmidt.
They piled on three converted tries to lead 21-0 at halftime at Suncorp Stadium and ultimately picked up a bonus point.
Australia's only try to centre Hunter Paisami came in the 76th minute when South Africa was down to 13 men.
"It's a tough learning for our group," Wallabies skipper and prop Allan Alaalatoa told Stan and Nine.
South Africa pressured Australia in the scrum and lineout and won the breakdown battle.
"They won the physical battle today," Schmidt said.
"Their breakdown was really strong and they dominated possession and territory in that first half which saps the strength out of the boys a little bit, but I was proud of the way the team hung in there and fought back."
Schmidt singled out lock Nick Frost for his performance.
"I thought he was a champion today, worked really hard, did some really good work in the physical areas and I think he can be proud of the effort he put in," Schmidt said of Frost.
However, the coach revealed Frost, replacement lock Jeremy Williams and winger Filipo Daugunu, who came off in the first half, all suffered knocks.
South Africa supplemented their traditional power game with some sparkling ball movement and could have scored more tries, suggesting new attack coach Tony Brown is adding another element to an already formidable side.
"It's just the hunger, the desperation of wanting to make sure that we do well because we know these two matches (against Australia) can win you the Championship or they can lose the championship," Springboks captain and flanker Siya Kolisi said.
Kurt-Lee Arendse scored two tries for the Springboks. (Jono Searle/AAP PHOTOS)
The Springboks were twice down to 13 men inside the last 15 minutes after replacement forwards Malcolm Marx and Marco van Staden and centre Jesse Kriel were sin-binned.
Lack of discipline cost Australia in the first half as they gave away eight penalties and had winger Andrew Kellaway sin-binned on the half hour for a lifting tackle on Springboks halfback Cobus Reinach.Â
Highly touted Springboks five-eighth Sacha Feinberg Mngomezulu missed a relatively easy early penalty attempt but troubled the Wallabies defence with his smart options as he feasted on a glut of possession provided by his forwards.
South Africa opened the scoring In the ninth minute through Kolisi, who dived over off an unstoppable drive following a clever lineout variation by his side.
Du-Toit, rounded off an eight-phase move to cross for their second try and winger Kurt-Lee Arendse showed great footwork for the third, stepping his way past three defenders.
Australia had few crumbs of possession in the first half, but showed more enterprise in the first 20 minutes of the second half until replacement forward Kwagga Smith bulldozed his way over for the Springboks' fourth try just after the hour.
Almost straight from the restart, Kriel cut through the defence, beating three defenders and set up Arendse for his second try.
Brumbies flanker Luke Reimer made his Wallabies debut off the bench, joining starter and fellow back rower Carlo Tizzano in earning a first Test cap.
The teams clash again next Saturday at Perth's Optus Stadium.
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