Australia spinner Nathan Lyon put the visitors on the front foot by removing Dean Elgar and Hashim Amla in quick succession as South Africa laboured to 55-3 at tea at Kingsmead in Durban.
Pat Cummins dismissed Aiden Markram, who was starting to look good for the home side on 32, with the last ball before tea.
Markram had taken the challenge to the Australian bowlers early on, but the complexion of the innings changed when Steve Smith introduced Lyon to the attack.
The off-spinner struck with his second and fourth balls as he sent Elgar (7) and Amla (0) back to the change room.
Captain Faf du Plessis will join AB de Villiers in the middle after tea.
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Earlier, Australia had recovered from 251-7 to post 351 all out.
Lyon and Mitchell Marsh began the second session in the middle for the Australians, who were looking to frustrate the home side and make a respectable first-innings total.
The message from the dressing room to Lyon must have been ‘stick around’ as he wasn’t looking to play expansively.
Marsh, who had been brilliant throughout the innings, was finally out for 96 when he looked to go over the top off a Vernon Philander delivery, but instead found the tallest man on the field in Morne Morkel.
Marsh and Lyon had put on a brisk 41 runs for the ninth wicket as they continued to frustrate the South Africans.
Josh Hazlewood was the last man in for the visitors, who at that point were 341-9.
They were soon 350-9 when Lyon swept Keshav Maharaj for four. But the spinner, playing on his home ground picked up his fifth wicket when Lyon looked to go over the covers, but found Theunis de Bruyn.
Maharaj was the pick of the South African bowlers with figures of 5-123.
The South Africans started their innings well as Markram laid down the challenge with a number of beautiful shots as he raced to 20 off 24 balls.
But, as things were looking good for the home side, Smith brought on off-spinner Lyon, who made the all-important breakthrough when he caught Elgar off his own bowling for just seven.
Amla’s time in the middle lasted just two balls as he was caught by Cameron Bancroft off Lyon, who picked up his second wicket in his first over.
Markram, who had played well, was out for 32 when he was caught by Bancroft off the bowling of Cummins.
Photo: Lee Warren/Gallo Images