De Kock laid the platform for the win alongside opening partner Rilee Roussow as the pair belted 145 off the opening 17 overs of the run chase.
With frontline quicks Mitchell Starc, Josh Hazlewood and James Faulkner all resting at home, Australia's remaining fast bowlers had little answer to the onslaught in the thin air of Centurion.
Roussow, playing in place of the sick Hashim Amla, raced to 65 off just 44 deliveries before he was trapped LBW off Adam Zampa's first delivery of the match.
But Zampa's success just spurred de Kock on, bringing up his 11th career ODI century off just 74 deliveries.
None of Australia's bowlers escaped the carnage.
Scott Boland finished with 3-67, including the wicket of de Kock, but went at just under 10 runs an over.
Daniel Worrall, in just his second ODI appearance, went for 0-50 off 7.2 overs.
Mitchell Marsh (0-66) went at eight runs an over, John Hastings (0-52) at sevens while even leg-spinner Zampa (1-44) went at over eight runs an over.
De Kock's efforts put Australia's batting to shame, half-centuries to George Bailey (74) and Hastings (51) lifting them near 300 after tumbling to 6-192 at one stage of their innings.
Young South African quick Adile Phehlukwayo, in his second ODI appearance, was the pick of the hosts' bowlers with 4-44 off his 10 overs.
Veteran quick Dale Steyn (2-65) marked his return from almost a year out of South Africa's ODI team with two late scalps.
The series continues on Sunday with game two at the New Wanderers Stadium in Johannesburg.
- AAP
