Man-of-the-match Smith cracked 104 off 112 balls as Australia stormed home to overhaul South Africa's 267 for eight to win with an over to spare.
The victory wrapped up the ODI series 3-1 over the Proteas ahead of Sunday's final game in Sydney.
The Proteas looked in control for most of Australia's innings, reducing the home side to 98 for five in the 25th over, before Smith turned the tide with a ground record 121-run sixth-wicket stand with wicketkeeper Matt Wade.
When Wade was brilliantly caught in the outfield by a diving Ryan McLaren for 52 off 94 balls, James Faulkner came in and took up where Wade left off slamming an unbeaten 34 off 31 balls with six fours.
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Smith has proved the thorn for the Proteas in this series, hitting an unbeaten 73 to help the Australians win in the third ODI in Canberra on Wednesday.
He was annoyed to be bowled by Robin Peterson as he attempted to go after the winning run, but the damage had been done for South Africa.
"And Faulkner came out and did what he has done so well over the last year and finish off the innings. It's another series win for us, which is great."
The match finished on a video umpire's adjudication after Pat Cummins appeared to be caught by a diving David Miller, only for the decision to be reversed when replays showed the ball had bounced before Miller's hands.
That proved to be the winning run as Cummins and Faulkner crossed for the Australians to celebrate a psychological series victory ahead of next year's World Cup in Australia and New Zealand.