Mitchell Marsh will captain an Australia team featuring a new-look middle order and bowling attack against the Proteas in Bloemfontein on Thursday.
Regular captain Pat Cummins will miss the first ODI of the five-match series as he recovers from a wrist injury.
Veteran opener David Warner will open the batting after missing the T20I series, which the visitors won 3-0 under new skipper Marsh.
Both wicketkeepers in Australia’s World Cup squad, Alex Carey and Josh Inglis, will bat in the middle order, while all-rounders Cameron Green and Marcus Stoinis will be used at No 4 and No 7 respectively.
Australia XI: David Warner, Travis Head, Mitchell Marsh (c), Cameron Green, Josh Inglis, Alex Carey, Marcus Stoinis, Sean Abbott, Ashton Agar, Josh Hazlewood, Adam Zampa.