Captain Mitch Marsh had looked set to blast the visitors to an opening victory against a callow Proteas' bowling attack but after he'd perished to the spinning wiles of Kehav Maharaj, none of his team were able to build on decent starts as the world champs collapsed to 230 all out in pursuit of their 298-run target.
The South Africans had set a challenging target after being inserted by Marsh, compiling 8-297 thanks largely to a brilliant 112 from Matthew Breetzke and a spectacular 75 off 59 balls from lanky pace-bowling allrounder Marco Jansen.
Marsh, standing in as skipper again for the rested Pat Cummins, led from the front in response with his 60 off just 36 balls while sharing an opening stand of 90 in just 9.2 overs with Travis Head.
But Head (36), Cooper Connolly (38) and Matt Renshaw (44) also all gave up their wickets too easily when Australia seemed to be in command, their soft dismissals only putting them under pressure when there didn't seem to be any.
The superb spinning of Maharaj (4-20) and Bjorn Fortuin (2-34) then increasingly discomfited the visitors, as Marsh's men lost their last six wickets for just 54 runs to allow the Proteas to draw first blood in the three-match series.
"I'm pretty disappointed," Marsh admitted. "South Africa outplayed us. It was a good game of cricket but we fell well short.
"We had our opportunities, I am probably going to sound like a broken record speaking about having partnerships in our batting, but we weren't able to form many tonight."
The key moment may have been when Jansen took a sensational running, diving, one-handed catch in the outfield, stretching out his long telescopic arm to scoop up the ball just above the turf to get rid of Renshaw off Gerald Coetzee. It left Australia on 7-215, and there was no way back.
So, after the three-match sweep of the Zimbabwe series, this felt much more like a real test of Australia with the defence of their 50-over World Cup in southern Africa just a year away, and the first part of the reconnaissance mission demonstrated just how much they still have to work on.
Man-of-the-match could easily have been Jansen, with his one wicket, four catches and big-hitting or the superb 36-year-old veteran tweaker Maharaj, but batting at No.4, Breetzke's superb 106-ball knock, before being run out by Connolly, deservedly won the day.
There was the odd encouraging performance for Australia, who gave allrounder Jack Edwards an uncomfortable debut -- 0-56 off 10 overs, followed by scoring five off 15 balls -- particularly from paceman Nathan Ellis, who, fresh from his outstanding series against Zimbabwe, was again the bowling pick with 3-57.
Allrounder Cameron Green, back in the side after missing the series against Zimbabwe as he recovered from a shoulder injury, had a poor day with the bat, falling for five while trying needlessly to belt Maharaj over cow corner and getting caught in the deep.
The opening loss has really put pressure on Australia to turn the series round at The Wanderers in Johannesburg on Sunday, when Cummins is likely to be ready to be recalled. They haven't won a bilateral series against South Africa since 2014.