It is a familiar feeling of late against the South Africans, as in their 24 ODI meetings since September 2016, Australia have won five times and lost 18, with one match abandoned.
With the 2027 World Cup to be staged in South Africa, Namibia and Zimbabwe around this time next year, the three-match series will be an invaluable experience for Australia.
They had a stranglehold on the South African batting early in the innings but allowed them to reach 297-8 in their 50 overs.
Australia then raced to 90 without loss from 9.2 overs and looked imperious, but lost 10 wickets for the addition of another 140 runs to be well-beaten.
"They (South Africa) got 100 runs off the last 10 overs," Australia captain Mitch Marsh said.
"They like to build in their 50 overs and then go hard in the last 10 or 15. We pushed to try and get an extra couple of wickets (to prevent that), but it didn't go our way.
"Credit where it is due, they did well to get (close to) 300 on that wicket."
Marsh was superb at the top of the Australian order in reply with 60 from 36 balls, but once he was out off the bowling of spinner Keshav Maharaj (4-20), the innings fell away.
"We managed to get the run rate down, from there it was about forming partnerships," Marsh said. "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.
"We knew with (Keshav) Maharaj and (spinner Bevan) Fortuin, it was going to be key the way we played them. Unfortunately they were able to execute well for long periods of time."
The second match in the three-game series is in Johannesburg on Sunday.