In the second match of the one-day international triangular series in Harare, and the first involving these two sides, Aaron Finch's hundred looked to have put Australia at a commanding position at the halfway stage.
With openers Hashim Amla and Quinton de Kock back in the pavilion inside the opening 10 overs, the South Africans looked to have it all to do in their reply.
But De Villiers and Du Plessis combined beautifully, adding 206 for the third wicket before the latter was dismissed for 106 by Mitchell Starc (2-62 from eight overs).
His captain remained however, finishing unbeaten on 136 - the second-highest score by a South African against Australia in ODIs - and both sides now have one win apiece to their name, after Australia's 198-run demolition of Zimbabwe on Monday.
Australia made one change from that game, with Phil Hughes replacing Nathan Lyon, and the left-hander opened the innings alongside Finch.
The pair put on 92 before Hughes departed for 51 to Imran Tahir (2-45 from 10), while Finch then added 114 with stand-in skipper George Bailey (66).
Finch had made 102 when he was ousted by Ryan McLaren (2-64 from nine), while late hitting from Steve Smith (31 off 19 balls) and Mitchell Johnson (23 not out off eight) added some late impetus.
South Africa's chase started well but soon faltered after Kane Richardson (1-68 from 10) picked up the key wicket of Amla for 24, well held by Smith diving low at backward point.
De Kock followed in the next over for 19 thanks to another excellent catch by James Faulkner, and his demise brought De Villiers to the middle.
He and Du Plessis set about rebuilding the innings, combining superb running between the wickets with devastating strokeplay.
Australia will rue two bad misses off De Villiers in consecutive overs, Johnson spilling a simple return chance when the batsman was on 78 and Bailey fumbling another straightforward catch at backward point when he was 85.
Both batsman brought up three figures - Du Plessis for the first time in ODIs - in the 38th over from Starc.
And, although Du Plessis fell in that same over, De Villiers - suffering from chronic cramp - was ably supported by JP Duminy (33 not out) as South Africa reached their target with 20 balls to spare.