Despite reducing the home side to 12 for 3 in reply, South Africa was dismissed for just 76 runs.
Australia's fast bowlers braved the searing heat at the WACA to dismantle an inexperienced South Africa side sorely missing Marizanne Kapp, but captain Alyssa Healy fell just short of her maiden Test century at the close of the first day.
After a long day in the field, Healy was dismissed for 99 when she was caught and bowled off debutant Delmi Tucker's off-spin.
In the historic first Test between the two countries, Australia led by 175 runs at the stumps.
In 31.2 overs, South Africa was bowled out for just 76, their lowest-ever Test score. But the Australians responded with the help of Masabata Klaassen's spectacular new-ball knock to leave the hosts reeling at 12-3.
Healy and Beth Mooney put on a 155-run partnership to reassert Australia's dominance as the South African attack struggled to maintain pressure in 42-degree heat.
Healy teamed up with Annabel Sutherland, who capitalised on a faltering South Africa with an unbeaten half-century as the shadows crept over the ground.
After a disastrous start to the four-dayer, South Africa's bid to snatch a come-from-behind victory to level the multi-format series looks unlikely.
Playing only their second Test in a decade and fielding four debutants, South Africa was shaken when Kapp withdrew through illness.
South Africa struggled to handle the precise and disciplined bowling of Australia's fast bowlers, who effectively targeted a dangerous back-of-a-length area. The South African team's lack of experience with red-ball cricket was evident as they succumbed to loose shots. Their batsmen were undone by poor footwork and frequently played rash shots outside the off-stump.
In a bold decision, Healy opted to bowl first despite the sweltering heat, with speedster Darcie Brown taking her first Test five-wicket haul, while Sutherland and Tahlia McGrath also batted well on a green-tinged surface that offered movement and bounce.
The quicks' dominance meant Healy did not have to call on Australia's trio of frontline spinners, including Sophie Molineux, playing her first international for over two years.
In the first men's or women's Test match played at the WACA since December 2017, pace-bowling dominated.
Brown, who won back her spot after missing Australia's last Test in India, created a chance almost immediately when opener Anneke Bosch was dropped at third slip by Mooney.
However, Laura Wolvaardt, the captain of South Africa, was unable to overcome her sluggish form on the tour and was worked over by a fiery Brown. Although South Africa appeared to be rallying when Sune Luus and Tazmin Brits dug in to defy Australia for 12 overs, Wolvaardt was unable to capitalise on a drop from a diving Healy and fell on the next delivery to Brown, who finished a spectacular opening spell with 2 for 5 from five overs. However, Brits was unable to rotate the strike and crawled to 5 off 48 balls before being dismissed lbw by Sutherland. The decision was overturned on DRS. As South Africa spiralled, Tucker had a horror debut, chopping on to her stumps with the first ball of the innings.
Luus was the only batter who did not seem overawed by the situation and made a fluent 26. However, she was lured into a drive by Sutherland, providing more catching practice for the slips.
In danger of being bowled out within the session, South Africa offered little resistance. The hosts trudged to lunch on 55 for eight, but could not beat their previous lowest Test score of 89 against New Zealand in Durban in 1972.
Klaas fought back with the ball and maintained her stranglehold on Litchfield, who edged to third slip after being lured into driving a wide ball. Klaas then dismissed Ellyse Perry and McGrath cheaply as South Africa made a comeback.
But before Australia could accelerate their scoring, the experience of Mooney and Healy helped them recover. Healy was in an aggressive mood and raced to a half-century in just 59 balls with a powerful shot through midwicket. Shortly after, Mooney also reached her half-century.
South Africa struggled in the hot weather and seemed to be going through the motions until Nadine de Klerk took a wicket out of nowhere by having Mooney caught at a wide slip.
Healy looked tired and was dismissed just before stumps, but her team remained in control.