Australia A were bowled out in their second innings at 310 for nine, having built a lead of 17 runs, according to a Cricket Australia release.
Australia A's Moises Henriques did not bat in the second innings due to groin soreness and will undergo further assessment.
South Africa A took less than four overs to reach the set target, finishing 18 for two to claim an easy eight-wicket win.
Tom Cooper was the leading run scorer for Australia A, finishing with 82 runs, while Matthew Wade (60) also notched a half century.
Simon Harmer was the pick of the bowlers for South Africa A, finishing with three for 106.
In the first innings, South Africa A riding on Rilee Rossouw's magnificent 231 and Temba Bavuma's 162 posted a mammoth score of 532 for eight declared.
South African pacer Marchant de Lange took four wickets as Australia A were bowled out for 239 and made to follow on.
The two teams will meet in the second four-day match at Tony Ireland stadium starting Thursday.
South Africa A: 532 for eight declared (Rilee Rossouw 231, Temba Bavuma 162; Gurinder Sandhu 4-77) and 18 for two (Rilee Rossouw 13 not out; Marcus Stoinis 1-9)
Australia A: 239 all out (Peter Nevill 53 not out, Callum Ferguson 47, Marchant de Lange 4-53) and 310 for nine (Tom Cooper 82, Mathew Wade 60, Simon Harmer 3-106)