The 23-year-old racked up 178 runs from 113 deliveries in a barnstorming innings, falling just 10 short of Gary Kirsten's 20-year-old ODI record for South Africa.
With the tourists having posted a score of 294-9, De Kock wasted little time in making inroads and plundered 16 fours and 11 maximums during his stunning display.
After winning the toss and electing to bowl first, the Proteas were somewhat reliant on youngster Andile Phehlukwayo to contain Australia, who made a promising start by reaching 88 for the loss of one wicket.
Playing in his second ODI, Phehlukwayo took 4-44 from his 10 overs, claiming the consecutive scalps of Aaron Finch (33), Steve Smith (8) and Mitchell Marsh (31) having already supplied the catch as David Warner (40) fell first.
It was also Phehlukwayo who halted the charge of John Hastings, who posted 51 from 56 deliveries, leaving the tourists 271-7.
Standout performer George Bailey (74) was finally felled when he was caught by David Miller off Dale Steyn's (2-65) delivery in the 48th over, and South Africa were left chasing a winning target of 295.
Rilee Rossouw (63) proved a capable accomplice to De Kock in the early stages of the South African innings.
His sixth ODI 50 contributed to a 145-run partnership that had the writing on the wall for Australia by the time he was trapped lbw by Adam Zampa (1-44).
Faf du Plessis' 26 was something of a sideshow compared to the limelight-hogging heroics of De Kock, who continued to find the boundary on a regular basis, bringing up his 100 with a six.
De Kock had the double century - a feat achieved on just six previous occasions - in his sights, but JP Duminy (9) arrived at the crease intent on simply getting the job done.
His two boundaries took another chunk out of the target before De Kock was eventually dispatched by Scott Boland (3-67), with Travis Head making the catch.
But the damage had already been done for Australia and David Miller's (10 not out) single wrapped up a deserved win.