Set a mammoth target of 430 for victory, the tourists' chase began disastrously, captain Graeme Smith out for a duck with the sixth ball of the innings and three more wickets tumbling quickly in the afternoon heat at Adelaide Oval.
Wicketkeeper batsman AB de Villiers and Faf du Plessis dug for more than an hour and a half, but South Africa staggered to 77-4 at the close, trailing their target by 353 runs.
De Villiers was on 12 and Du Plessis on 19, with injured Jacques Kallis the last recognised batsman in the Proteas' dressing room.
South Africa's hopes may again rest on all-rounder Kallis, who battled a hamstring strain to score a half-century in the first innings and help the tourists avoid the follow-on.
With Smith and number three Hashim Amla out before tea, Jacques Rudolph and opener Alviro Petersen resumed at 40-2 but their partnership lasted only five more runs before spinner Nathan Lyon claimed his second wicket of the innings.
Lyon, who two years ago worked as a groundsman at Adelaide Oval, had Rudolph poke the ball to Ed Cowan, who lunged low and to his left to take a sharp catch at short leg.
Out for three, Rudolph's dismissal was his fourth at the hands of the 25-year-old offspinner from four innings in the series.
Petersen's celebrations for his 32nd birthday were tempered an over later, when he was out for 24, dragging a Peter Siddle delivery onto his stumps to leave his team reeling at 45-4.
Charged with steering South Africa to safety, De Villiers and Du Plessis slowed their scoring to a crawl, with any thoughts of victory apparently banished.
The pair added only 10 runs in little more than an hour after the drinks break of the last session, looking determined not to play any offensive stroke if it could be helped.
Any wafer-thin South African hopes may lie with the Australians running out of steam on the final day, with paceman James Pattinson ruled out for the remainder of the series with a rib injury and Australia's bowlers forced to shoulder a greater workload.
The news marred a dominant day for the hosts, who resumed on 111-5 and declared after lunch at 267-8 following a feisty ninth-wicket stand of 47 from Pattinson and Ben Hilfenhaus.
Smith, who anchored the tourists' first innings with a defiant century, was out for a second-ball duck when sent a thick edge Ricky Ponting at second slip.
Amla and Petersen added 33 runs for the second wicket before Lyon struck to remove Amla for 17 off 36 balls, caught behind by Australia captain Michael Clarke at slip.
South Africa had torn through Australia's batsmen with five wickets after tea on the day three, but their faint hopes dimmed when Clarke and Hussey dug in for 62 runs in the morning.
Clarke, on a pair of double-centuries, was eventually trapped in front by Dale Steyn for 38, while Hussey added a 54 to his first innings 103 before he skied a simple catch to the paceman just before lunch.
- Sports & Recreation
- South Africa
- Graeme Smith
- Jacques Rudolph
- Alviro Petersen