After taking six wickets on the opening day to help set up the Test for Australia, Starc removed openers Aiden Markram and Marques Ackerman on Thursday.
His double blow came after a second Test century for Josh Inglis had helped lift Australia to 429 in their first innings early on day three, in reply to the Proteas' 329.
The third and deciding Test still remains somewhat in the balance, with a fourth-innings chase looming as tricky on a wicket that's offering plenty of turn.
But thanks to Starc (2-29) and Nathan Lyon's crucial late dismissal of stubborn homer skipper Temba Bavuma, Australia can for now claim the upper hand.
South Africa were guilty of throwing away some of their wickets on Thursday, with Markram driving Starc straight to Travis Head at mid-off for two.
David Bedingham then top-edged a Josh Hazlewood short ball to deep backward square on 11, after being one of three Proteas caught hooking in the first innings.
And while Marques Ackerman and Bavuma appeared to have steadied the ship for the Proteas, it was a brute of a ball from Starc that broke a 64-run partnership.
Brought back on midway through the last session, the left-armer had a bouncer follow Ackerman as he tried to uppercut on 62.
It hit the left-hander's bat and helmet on the way through to the slips, leaving the Proteas 3-95 and still five runs short of drawing level.
Ackerman did try to review the call and was told to start walking by Head with time having just elapsed, but replays showed the call would not have been overturned anyway.
Lyon then bowled Bavuma for 35 just five minutes before stumps, when the Proteas captain inexplicably tried to hit hard across the line with the offspinner getting prodigious turn.
Pat Cummins has again gone wicketless, with his drought now extending to 358 balls and back to the first Test in Durban.
But he still bowled particularly well, with Bavuma edging Australia's captain to just in front of slip and surviving an lbw review on height.
South Africa have not lost a home Test series for almost six years, and now need a serious recovery effort in a three-match contest full of twists and turns to keep that record.
Earlier, Inglis's century headlined one of Australia's most complete batting performances in years, with Alex Carey (80), Matt Renshaw (74) and Cameron Green (65) also posting half-centuries.
Cooper Connolly also made a crucial 29 alongside the lower-order, helping add another 49 for the final few wickets after Australia lost 3-10 on Thursday.
Those extra runs could prove crucial, with the pitch showing signs of turn and spinner Simon Harmer taking 4-107 for the Proteas before Lyon's late work.
After being called in late to replace the injured Steve Smith, Inglis brought up his hundred when he reverse-swept Harmer to the boundary.
At that point the Proteas had started the day reasonably flat, with a number of misfields at Newlands under the warm Cape Town sun.
But when he was caught behind later in the same Harmer over and a 185-run stand with Carey was ended, the Proteas were suddenly back in the contest.
Carey edged Harmer to slip four overs later, before Pat Cummins was trapped lbw by Kagiso Rabada in the mini collapse.
