Ben Alexander and Digby Ioane crossed for first-half tries, with James O'Connor, Stephen Moore and Adam Ashley-Cooper touching down in the second half to give the Wallabies a bonus point victory in front 52,788 people at Sydney's Olympic stadium.
Australia - back to its strongest lineup after its second-string side lost to Samoa - led from the eighth minute against a South Africa team missing most of its stars due to injury.
"We were confident but you never presume," said Australia coach Robbie Deans. "The boys adjusted their positions and we played some rugby this week.
"The boys who played last week were better for it and the guys who didn't probably got a shot over the bow."
South Africa coach Peter de Villiers was without many first-choice regulars, with 21 players unavailable for the away legs of their Tri-Nations campaign.
Among the absentees are locks Victor Matfield and Bakkies Botha, backrowers Schalk Burger and Juan Smith, winger Bryan Habana, scrumhalf Fourie du Preez and center Jaque Fourie.
Wallabies flyhalf Quade Cooper - playing despite suffering the effects of a stomach illness - was dominant throughout in his first test appearance of the season, frequently breaking the defensive line and finding space for his supporting backs.
"He did a good job," said Deans. "He carried very well and defended very well. You've got to dent the line. Get some momentum and play off it."
O'Connor scored 19 points, from a try, four conversions and two penalties. For South Africa, Morne Steyn landed two penalties and reserve fullback Pat Lambie converted tries from Chiliboy Ralepelle and captain John Smit.
Australia hit the front after Cooper and Kurtley Beale combined in a 70-meter break downfield, before captain Rocky Elsom drew two defenders and popped for Alexander to score in the corner.
From the resulting restart, scrumhalf Will Genia broke a weak attempted tackle by Smit and burst into space before finding Ioane, who shrugged off Springbok fullback Gio Aplon to score.
South Africa stayed in touch through two penalties from Steyn, but the Wallabies again burst into life by scoring three tries in the space of 12 second-half minutes to secure a bonus point for scoring four or more tries in the match.
O'Connor scored a deserved try on 43 minutes after showing good skills to collect a low pass from Quade Cooper, after the flyhalf had again broken the South African defensive line with an angled run.
Five minutes later, Moore scored Australia's fourth try, barging over from short range against some weak South African defense around the ruck.
Adam Ashley-Cooper completed the rout on 55 minutes, completing a swift Wallabies backline move to score in the corner.
"They (the backs) looked pretty sharp when they got an opportunity," said Wallabies captain Rocky Elsom. "At the crucial times we stood up.
"That was the most pleasing thing. It put us on the front foot, gave us the advantage."
Kurtley Beale limped off late in the match with what appeared an ankle injury. The last time the two nations met, Beale kicked a penalty after the fulltime siren to give Australia a 41-39 victory and its first win on the high veldt in 47 years.
The Springboks scored two late tries to narrow the deficit, but the weakened team always struggled to find any rhythm in attack and missed far too many tackles against a strong Wallabies attack.
South Africa has an opportunity to bounce back when it plays New Zealand in Wellington on Saturday.
Australia plays New Zealand in Auckland on August 6. Deans said: "It was a step forward, but there's going to have to be another one," he said. "We have a bit of time off now to refocus and work on some things before Eden Park."
