Legspinner Tanveer Sangha will make his one-day international debut for Australia, who have sent South Africa in to bat at Potchefstroom.
Sangha, who took 4-31 in a sparkling Twenty20 international debut earlier in the tour, has been rotated in for Tuesday's third ODI for fellow leggie Adam Zampa.
Australia, who lead the series 2-0, can seal the five-match contest with victory at JB Marks Oval.
They have made two other changes with pace spearhead Josh Hazlewood and allrounder Marcus Stoinis returning in place of Josh Inglis and Aaron Hardie.
The Proteas have made four changes from the team that was humbled by 123 runs on the weekend.
Top-order batter Reeza Hendricks will make his first appearance in the series, seamer Gerald Coetzee returns and death-over specialist Sisanda Magada has been called up after being sidelined with a knee niggle.
Left-arm orthodox tweaker Keshav Maharaj comes back, joining wrist spinner Tabraiz Shamsi in a two-pronged spin attack which may prove a handful on a dry-looking surface.
Fast bowler Anrich Nortje is out with back spasms while Kagiso Rabada, Rassie van der Dussen and Andile Phehlukwayo have been left out.
Australia: Mitch Marsh (capt), Travis Head, David Warner, Marnus Labuschagne, Alex Carey, Marcus Stoinis, Tim David, Sean Abbott, Nathan Ellis, Tanveer Sangha, Josh Hazlewood.
South Africa: Temba Bavuma (capt), Quinton de Kock, Reeza Hendricks, Aiden Markram, Heinrich Klaasen, David Miller, Marco Jansen, Sisanda Magala, Gerald Coetzee, Keshav Maharaj, Tabraiz Shamsi.