The players failed to return to the pitch at Wanderers after South Africa's first innings ended late in the day, and stumps was called by the umpires with the light fading in Johannesburg.
Australia had to bowl spinners Lyon and Clarke from both ends just to stay on the pitch in the gloomy conditions.
De Villiers top-scored with 64, sharing a 112-run partnership with Prince (50) to save South Africa from an initial period of pressure at 129-4 soon after lunch after having opted to bat first.
But the Aussies who lost medium-pacer Shane Watson with a right hamstring problem turned the game in 44 minutes and just over 10 overs in the late afternoon.
After its shattering eight-wicket defeat at Newlands, Australia has to win to save its proud record in South Africa. It has not lost a test series here since 1970.
Lyon broke the De Villiers-Prince stand when Prince fell for 50 off 89 balls and Siddle removed De Villiers five balls later to a brilliant running, diving catch at mid-on by debutant Cummins, who took the ball with his back to the batsman.
Vernon Philander was lbw for a duck to Lyon and Mark Boucher (3) skied a shot down to Lyon at fine leg off Siddle, as South Africa went tumbling from 241-4 to 245-8 in 17 balls.
Clarke then removed Morne Morkel and Imran Tahir with little fuss, allowing Australia to power back into the two-test series.
Kallis and De Villiers led two separate fightbacks as South Africa initially recovered from 43-2 and 129-4, but it had no answer to the final period of pressure from Australia's bowlers.
"I think there were a lot of soft dismissals. At 240-4, you're dominating the game. We had far too many soft dismissals, if we're honest with ourselves," Kallis said. "There's a little but in that wicket. It's a little bit two-paced and the odd ball seems to stick in the wicket. Like I said, there's enough encouragement there but, as a whole, disappointing for us."
Kallis became just the fourth test player to pass 12,000 runs in a free-flowing 54 off 41 balls in which he hit eight fours and two sixes and scored 44 in boundaries to respond in an attacking manner to the early loss of openers Graeme Smith and Jacques Rudolph.
He passed West Indies' Brian Lara as the fourth highest scorer before lunch and then went past 12,000 with an edge through slips for four.
But he was out next ball when he nudged Siddle's delivery straight to Usman Khawaja at midwicket.
Having bowled with impressive pace throughout the first session, the 18-year-old Cummins (1-38) was rewarded in his first test when Hashim Amla found a delivery too quick and sent a flashing edge to Ricky Ponting in the slips, who held a sharp catch.
Cummins is now the youngest wicket-taker in tests for Australia after becoming the country's second youngest test debutant and its most youthful for nearly 60 years.
De Villiers repeated Kallis' tactics in deciding to take the attack to Australia, which was hampered by the loss of Watson after he had managed just 3.5 overs.
De Villiers carved out 11 fours in his 97-ball knock and Prince was just behind with nine fours off 89 balls.
But Lyon broke the partnership, Siddle had the crucial wicket of De Villiers straight afterward to a mistimed pull shot and Australia's ruthless finish to the day gives it hope of a winning comeback following a traumatic week.
- AP
