Labuschagne played only after Cameron Green suffered a head injury from a Marco Jansen 140 kph bouncer off his helmet before he scored.
The concussion substitute was allowed in at five down and Labuschagne watched two more wickets fall as Australia collapsed to 113-7 in the 17th over. They were chasing 223 to win on a pitch of variable bounce against fired-up South African quicks.
But Ashton Agar joined Labuschagne and they calmly picked off the runs in an unbeaten stand of 112 to lead Australia to a notable win by three wickets with nearly 10 overs to spare.
Labuschagne made 80 not out and Agar 48 not out in a remarkable show of cool resilience. They pocketed all flashy strokes and, with a run rate required of 2, sliced apart South Africa with ones and twos. They went more than 14 overs without hitting a boundary.
Agar hit the winning runs, a boundary through the covers.
“Gutsy win,” stand-in captain Mitch Marsh said. “(The) boys are unbelievable. We were lucky with Marnus coming in and taking us over the line. Marnus is the perfect man for the job. He gives it everything.”
South Africa was made to bat and was all out for 222 in 49 overs. Captain Temba Bavuma was 114 not out and the rest of the team scored 108.
Bavuma rode his luck. He was dropped on 6 and 88 and overturned a lbw decision against him on 24.
South Africa started slow — 25-1 after 10 overs — and plenty of batters got starts but only Bavuma could endure.
South Africa was down to 185-9 in the 44th and Bavuma was dropped a second time in the 46th by Alex Carey. But No. 11 batter Lungi Ngidi blocked expertly to support his captain.
Bavuma swept a boundary through midwicket to reach his fifth ODI century and third this year, and smacked three boundaries off Josh Hazlewood who, in the same over, claimed Ngidi to end the innings.
Bavuma was only the second South African opener to carry his bat after Herschelle Gibbs in 2000 against Pakistan.
Australia was too wild in its chase.
David Warner and Josh Inglis chopped on, Marsh nicked Kagiso Rabada, and Travis Head pulled Ngidi straight to Rabada. Gerald Coetzee dismissed Carey and Marcus Stoinis and Sean Abbott was bowled by Maharaj.
They were seven down in less than 20 overs. Labuschagne and Agar pulled off the escape.
The second of five ODIs is on Saturday.
AP cricket: https://apnews.com/hub/cricket