Australia will bowl first against South Africa in Johannesburg, where they are out to avoid a record-breaking sixth straight Twenty20 loss.
Steve Smith won the toss at the Wanderers and revealed four changed to the XI that lost by three wickets at Durban.
Paceman Josh Hazlewood and allrounders Shane Watson and James Faulkner were recalled, while Ashton Agar is making his T20 debut.
Opener Usman Khawaja, legspinner Adam Zampa and quicks Nathan Coulter-Nile and Andrew Tye were omitted.
Selectors are using the three-match series to work out their best XI before the T20 World Cup starts later this month in India.
"It's part and parcel of the game (making so many changes to the side)," Smith said.
Fit-again spearhead Dale Steyn has recovered from a shoulder injury and will play his first game for the Proteas since their Boxing Day Test against England.
Australia lost three T20s at home against India earlier this year, while they were defeated by five runs in a T20 against England that followed the 2015 Ashes.
The side has never lost six T20s in a row.
Australia XI: Aaron Finch, Shane Watson, Steve Smith (capt), David Warner, Glenn Maxwell, Mitch Marsh, James Faulkner, Ashton Agar, Peter Nevill, John Hastings, Josh Hazlewood.
South Africa XI: Quinton de Kock, AB de Villiers, Faf du Plessis (capt), JP Duminy, David Miller, Farhaan Behardien, David Wiese, Chris Morris, Kagiso Rabada, Imran Tahir, Dale Steyn.
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