The touring side moved 2-0 up in the five-match series as the teams prepare for next month's World Cup in India with Australia scoring 392-8 after being put into bat and bowling out South Africa for 269.
Warner bludgeoned 106 off 93 balls as Australia got off to a speedy start and Labuschagne scored 124 off 99 in a performance that again questioned the decision to leave him out of the World Cup squad.
He had only travelled to South Africa as a replacement for injured Steve Smith but scored 80 not out to see Australia to victory in Thursday’s opening game and was man of the match again.
Warner and Travis Head set off at a furious pace as Australia reached 101-0 inside 10 overs before Head was spectacularly caught by a flying David Miller off Tabraiz Shamsi for 64 off 36 balls.
Spinner Shamsi removed Australian skipper Mitchell Marsh next ball but that did not put the brakes on the visitors with Warner and Labuschagne adding 151 runs for the third wicket.
Warner’s ton was his 20th in ODIs while it was only the second for Labuschagne, who hit 19 fours and a six.
There was also a rapid 50 off 37 balls from Josh Inglis as South Africa’s attack went to all corners and Australia set a formidable target, seven runs short of the record target they set England in 2016.
Quinton de Kock (45) and Temba Bavuma added 81 for South Africa's first wicket but the wrist spin of Adam Zampa (4-48) dismissed Bavuma 46 and Heinrich Klaasen for 49.
When David Miller (49) was trapped lbw by Nathan Ellis, South Africa’s hopes were realistically over and they were all out in the 42nd over.
The third ODI is in Potchefstroom on Tuesday.
