The hosts, needing 546 to win and level the three-match series, were dismissed for 370. The victory ensured Australia retained their number one Test ranking.
South Africa came into the final day in Durban with hopes of gaining a draw but lost the key wicket of Jacques Kallis (93) early in the first session and never looked like saving the game thereafter.
Only Mark Boucher put up any resistance for the hosts with a gritty 107-ball 25.
The tourists skittled the Proteas for 370 for nine - Graeme Smith not coming out to bat due to a broken finger - with Simon Katich claiming three wickets.
Resuming the final day on 244 for two, Kallis was soon dropped for the second time in the innings, this time by Michael Clarke after also being let off the hook by Marcus North when on nought on the penultimate day.
Katich was the pick of the Australia bowlers with three for 45, while Siddle also claimed three at the cost of 61 runs, the sportinglife.com reported.
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