Heinrich Klaasen's first one-day international century successfully set up South Africa for a 74-run win as Australia was bowled out for 217 while chasing 292 in the series-opener on Saturday.
Klaasen, often on the fringes of South Africa's limited-overs teams, made 123 not out from 114 balls as the home team posted 291-7 in Paarl. Klaasen had only one previous half-century in ODI cricket and was playing his first one-dayer in more than a year.
South Africa were 48-3 in the 10th over when Klaasen arrived and set about rescuing the innings with his seven fours and three sixes. David Miller supported with a 70-ball 64. Kyle Verreynne also helped with 48 on his ODI debut.
Australia threatened with an 84-run stand for the third wicket between Steve Smith (76) and Marnus Labuschagne, who made 41 against his country of birth.
Smith's dismissal lbw to fast bowler Anrich Nortje started a collapse, where the Australians lost their last six wickets for 43 runs to be bowled out in 45.1 overs.
Lungi Ngisi took 3-30 for South Africa and Nortje 2-39. Nortje ended it by knocking back Josh Hazlewood's off stump to put the Proteas ahead in the three-match series.