Captain Clarke blasted 39 fours and a six in a sparkling unbeaten 224 at Adelaide Oval to demoralise the Proteas after they lost paceman Vernon Philander before play started with a back injury and Jacques Kallis with a suspected hamstring injury after lunch.
Dale Steyn, the world's top-ranked Test bowler, took himself off after tea with another suspected hamstring strain, leaving the tourists at the mercy of a withering barrage from Clarke and fellow centurions David Warner and Mike Hussey.
"We just made 480 in a day, now I'm trying to work out what we've got to do tomorrow to set up this game to have a crack at winning," Clarke said after becoming the first player to score four double-centuries in a calendar year.
"It's a very good wicket. So there's a long way to go in this game before anybody wins but certainly for us, we need to really focused on tomorrow morning and continuing this momentum and making as many runs as we can in this first innings."
Steyn returned to the field and bowled Hussey with the last ball of the day but the horse had already bolted as Clarke and the rugged 37-year-old combined for a 272-run stand in bright sunshine.
That followed a thrilling 155-run partnership between Clarke and Warner after the hosts had slumped to 55-3 with Kallis striking twice in the morning to skittle the top order.
However, when Kallis went off injured, the pair hit out after lunch as South Africa captain Graeme Smith rested Steyn and threw spinner Imran Tahir to the wolves.
Clarke and Warner plundered 108 runs in less than an hour after lunch, with the latter lofting a six over bowler Tahir's head and then stroking a sublime cover drive for four on the next delivery to bring up his third test century.
Having had his place in the Test side questioned after an indifferent run of form, an ecstatic Warner bounded down the wicket and punched the air in delight as the fans squeezed into the half of the ground not under renovation roared.
The belligerent 26-year-old opener was eventually caught behind for 119 off the bowling of paceman Morne Morkel, having blasted 16 fours and four sixes, but Australia were in control at 210-4.
Clarke, in white-hot form following an unbeaten 259 in the drawn first Test in Brisbane, barely missed a step as he combined with Hussey after tea to drive Australia to their highest first-day total in decades.
The 31-year-old skipper brought up his first hundred with a cut to the backward point boundary off Tahir, having survived an appeal for caught behind when on 73 off the bowling of paceman Rory Kleinveldt that umpire Billy Bowden gave not out.
South Africa referred the decision but it was turned down after a video review, the second declined for the innings, leaving the visitors with no more referrals.
As shadows crept across the ground, Clarke began a renewed assault before stumps and charged to his 200th run with a single flicked off his pads to spark a standing ovation from a roaring crowd.
The crowd was back on their feet one ball later as Hussey slogged over midwicket for six to bring up his 17th Test century and second in succession after registering a ton in Brisbane.
South Africa's bowlers ended with ugly figures, with Tahir going wicketless for 159 runs, pillaged for more than seven an over. Kleinveldt, who replaced Philander in the team, battled hard but also went wicketless for 70 runs.
The tourists face a Herculean task to turn things around at Adelaide and could lose their top test ranking should they lose the three-match series.
Gary Kirsten said it was one of his toughest days as South Africa coach.
"We went through periods where we bowled quite nicely, but the periods where we didn't bowl nicely we got a beating," he said. "We're certainly not going to come here tomorrow thinking we're losing, that's for sure.
Kallis's removal of opener Ed Cowan for 10 with his third ball and Ricky Ponting for four underlined his importance to the team.
Morkel, who had Rob Quiney caught behind for a duck by Smith at first slip, finished with 2-128.