The Proteas fought back to win the series 3-2 after having been 2-0 down to convincingly win the last three matches ahead of the World Cup warm-up matches in India.
Australia had won the toss again and sent the home side into bat, with the pitch seemingly having enough green on it to be able to aid the seam bowlers.
However, the first wicket was the result of an unfortunate run out of South African skipper Temba Bavuma for a duck following a Marnus Labuschagne direct hit.
Bavuma had delayed taking off for the single called by his partner Quinton de Kock after taking a hit from a short ball from Sean Abbott.
De Kock, who was playing his final ODI match at The Wanderers ahead of his retirement from the format following the upcoming World Cup in India, was the next to go for 27 runs off 39 balls after a thick edge was well-caught by third slip Cameron Green off Nathan Ellis' bowling.
Aiden Markram joined Rassie van der Dussen with the score at 37/2 and the pair cautiously went about restoring balance in their innings before Rassie (30) drove a Sean Abbott half-volley straight into the hands of short extra cover Marnus Labuschagne.
Centurion hero Heinrich Klaasen (6) did not last long as his chief victim from the fourth ODI onslaught Adam Zampa avenged himself with a peach of a delivery that hit the 32-year-old's off stump to leave the Proteas at 103/4.
A steady 109-run partnership between Aiden Markram and David Miller steadied the innings and threatened to increase the tempo of the innings before Markram (93) was dismissed by Tim David on his first delivery in ODI cricket.
South Africa were able to push on in the final powerplay with David Miller (63), Marco Jansen (47 off 23 balls) and Andile Phehlukwayo (39 off 19) who scored three consecutive sixes and a four off the last ball of the innings, powering the home side to a good total of 315/9.
The Australians started their innings with their usual flurry of runs before David Warner (10) and Josh Inglis fell in quick succession to the inspired Marco Jansen with the score at 34/2.
Aussie captain Mitchell Marsh steadied the innings with Marnus Labuschagne before being dismissed by Jansen for 71 off 56 balls.
Man of the Match Marco Jansen continued to tear into the Australian top-order, claiming the wickets of Labuschagne (44) and Alex Carey (2) in the 21st over to leave the visitors reeling at 136/5 whilst claiming his first five-wicket haul in the limited overs format with figures of 5/39 in his eight overs.
Keshav Maharaj took over the mantle from the 23-year-old seamer, claiming the wicket of Tim David (1), Cameron Green (18), Sean Abbott (23) and Adam Zampa (5), with Andile Phehlukwayo also chipping in with the LBW dismissal of Michael Neser (5).
The Proteas will now embark on their trip to India where they are scheduled to face Afghanistan on Friday and New Zealand on the 2nd of October in warm-up fixtures ahead of their ICC World Cup opener against Sri Lanka on 7 October.