The teams were locked in a tense battle when bad light ended play on the fourth day Monday when Australia, needing 292 to complete a clean sweep of the series, were 248 for six. Damien Martyn was unbeaten on 93.
South Africa had led by 33 runs from the first innings after Australia managed just 270 runs in response to South Africa's first innings total of 303, but the hosts scored only 258 in their second innings to increase Australian hopes of snatching victory.
Injured opening batsman Justin Langer, who missed all of Monday's with a concussion, is unlikely to bat, so Martyn will need the support of his lower order batsmen to see Australia home.
"We've got to back our bowlers against their tail," said South African wicketkeeper Mark Boucher.
"The wicket has flattened out a bit but the history of the Wanderers shows that the ball does something early in the morning. We'll have to make sure our bowlers are fired up, we don't have any runs to play with."
The new ball is due after nine balls Tuesday.
Martyn and Michael Hussey (89) took Australia to within 94 runs of victory with a third wicket stand of 165 before a flurry of wickets lifted South Africa's hopes of avoiding the first whitewash series defeat on their own soil in 110 years.
"It was a lot of hard work and it was disappointing to get out at that time," said Hussey. "Another 50 runs in the partnership would have probably put it beyond doubt."
Both teams were without key players. Langer, who was concussed by a ball from Makhaya Ntini Saturday, was still out of action, while South African fast bowler Andre Nel left the field because of gastric illness after bowling only two overs.
Nel was expected to be able to play on the final day but Australian team spokesman Philip Pope said it was "more unlikely than likely" that Langer would bat, even in a close finish.
Boucher said that no-one liked to see a player get injured but warned that if Langer did bat he could expect no favours from the South African bowlers.
"There's a Test match up for grabs and if we have to win it by bowling short balls at him, so be it. I don't think he would expect us to lay off and we wouldn't expect the same from them."
Hussey said batting conditions remained difficult. "It's the sort of pitch where you can get a couple of wickets in a row. But we just need another good partnership now and hopefully we can get the last 44.
"It's going to be difficult but Marto (Martyn) has been playing brilliantly, Brett Lee is pretty capable and all the guys are determined to win the series 3-0."
South Africa quickly took the initiative at the start of the final innings and Australia were in trouble at 33 for two after losing opening batsman Matthew Hayden and captain Ricky Ponting.
But Hussey and Martyn batted solidly as they shared the biggest partnership of a match in which bowlers have dominated.
The left-handed Hussey, who opened with Hayden in the absence of Langer, survived two confident leg before wicket appeals and an appeal for a catch behind but then batted immaculately. "I definitely had my share of luck but you've just got to take it," he said.
Hussey was finally trapped leg before by left-arm spinner Nicky Boje after batting for 263 minutes and 197 balls.
Martyn had batted for 265 minutes and faced 184 balls, hitting 12 fours.
Earlier, South Africa added eight runs for the loss of their last two wickets, Australian bowler Brett Lee taking both wickets to finish with three for 57.
South Africa have not been beaten in every match of a home series of three matches or more since England won all three Tests in 1895/96 when South Africa were still finding their feet in international cricket.