Australia will need to reach a target of 129 to win the Twenty20 series over South Africa.
The Aussies, who have a 1-0 lead in the three-match series after the first match was washed out, won the toss and elected to field at Centurion.
Quinton de Kock and Hashim Amla opened the batting for the Proteas, but it was Amla who fell first when Mitchell Starc dismissed him for an lbw after taking two runs from three balls.
Faf du Plessis (5) shortly followed, while Jean-Paul Duminy was taken out by Glenn Maxwell for 13, with South Africa on 44 runs with the loss of three wickets.
De Kock led the attack for the Proteas, but he failed to reach a half-century as he was dismissed for 41, and the hosts closed the innings on 128-7.