On a horror fourth day for Australia, Marco Jansen bagged 5-33 as the tourists were all out in 42.3 overs and asked to follow on by the Proteas.
It marks the first time since 2019, and just the third time this century, Australia have been asked to do so.
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 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 Marnus 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 Nic Maddinson's first-innings duck on Tuesday night potentially making him the first to go.
Maddinson played and missed at one drive off Kagiso Rabada before edging his fourth ball to slip to leave Australia 1-3 at the end of day three.
Since his shock 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, before the quick removed Alex Carey for a duck later in the same over.
Another potential concern is Travis Head, who was lbw to a Jansen ball that seamed back a long way for 14 on Wednesday.
The South Australian had a superb first summer as opener in the Ashes last season on moving from No.5, but has now not passed 25 in his past six innings.
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.
Meanwhile, the Proteas have lost Nortje to a groin injury, after he limped off four overs into his spell on Wednesday.
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