After being asked to follow on for just the third time since 1988, Australia then went to tea on day four at 1-50 and still needing 276 runs to make the Proteas bat again.
On a horror fourth day for Australia, Marco Jansen bagged 5-33 as the tourists were all out in 42.3 overs in the first innings.
Nic Maddinson was then caught behind off Kagiso Rabada for eight before tea, marking his second failure for the match and likely ending his shock Test recall.
Marnus Labuschagne is 16 not out and fighting for his spot in the team, with Travis Head alongside him on 26.
After most of the first two days of this match were washed out and South Africa were at one stage 6-110, they are now in the box seat to level the series at 1-1 with one to play.
Steve Smith offered the lone first-innings resistance for Australia with 28, but battled a stiff neck in the process that at times had him batting front on to manage the situation.
But beyond this Test, and with a busy 10 months ahead, Australia have massive decisions to make, with Labuschagne among those in the gun.
Significant pressure is mounting after he edged Anrich Nortje on 14 and was superbly caught one-handed by Simon Harmer at slip on Wednesday.
The No.3 has not scored a Test century since the fourth Test of the 2023 Ashes, and was briefly dropped in the West Indies last year before forcing his way back in.
But since coach Andrew McDonald declared in August he "needs some big runs", Labuschagne has made scores of 4, 37, 37 and 14 against Bangladesh and South Africa.
The Queenslander may not even be Australia's biggest issue, with Maddinson's first-innings duck and second-innings eight potentially making him the first to go.
Maddinson played and missed at one drive off Rabada before edging his fourth ball to slip to leave Australia 1-3 at the end of day three.
He then hit the quick for two boundaries through the offside on day four, before again edging behind.
Since his recall in the first Test, Maddinson has now made scores of 0, 48 and 0 to leave his career average at 10.71.
Australia have Josh Inglis and Cooper Connolly as reserve batters on this tour, while Cameron Green bowled in the nets on Wednesday in a sign the allrounder is overcoming an abdomen strain.
They may need to move Matt Renshaw back up to the top of the order, after last week's Test heroics at No.5 had seen him remain in the middle at St George's Park.
Renshaw had offered some support to Smith on Wednesday before edging Jansen to slip on 12, with Alex Carey caught behind for a duck later in the same over.
Another potential concern is Head, who was lbw to a Jansen ball that seamed back a long way for 14 in the first innings on Wednesday.
The South Australian had a superb first summer as opener in the Ashes last season on moving from No.5, but had not passed 25 in the five innings prior to this Test.
Beau Webster also only managed an uncomfortable 13 on Wednesday as questions hover over his future, but the fact Green is not bowling on this tour could play into his hands.
Australia's capitulation came after the St George's Park wicket looked easy for South Africa to bat on on Tuesday, with Temba Bavuma hitting 179, Jansen 85 and Harmer 82 in their 9(dec)-425.
The Proteas have lost Nortje to a groin injury, after he limped off four overs into his spell on Wednesday.
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