The veteran pace ace struck twice on Thursday afternoon to leave the Proteas 4-140 in their second innings, leading by just 40 after three days, with Australia now firmly on top.
The left-armer's wickets came after he also took six on the opening day, setting up the match for Australia and giving them the best of the batting conditions.
But it's the way the pitch acted with Starc and Nathan Lyon bowling late on day three that offered a hint of the challenges Australia could face while chasing in the series decider.
Puffs of dust regularly exploded when Starc's deliveries hit the pitch late in the day, while Lyon was able to get bite with his off-spin and bowled Temba Bavuma in a key late strike.
South Africa spinner Simon Harmer took 4-109 in Australia's first innings, and looms as a threat if Australia have anything sizeable to chase on day four or five.
"If you look at how the wicket changed from this morning to this evening, there's been quite a dramatic change," Harmer said.
"Mitchell Starc does a pretty good job of churning up the wicket.
"So I definitely think spin is probably going to come into it a lot more than it has in the first two-and-a-half days.
"I think it was quite evident to see tonight how the ball was turning out of the footmarks."
Harmer's comments came as Australia's centurion, Josh Inglis, predicted anything more than 200 could become tough to chase.
"The further it goes into the game, I think it's only going to get harder and harder," Inglis, who spent more than three hours at the crease for his 102, said.
"I think it depends how long they bat for as opposed to runs.
"But you don't want to go too many more than maybe 200 or so. It's obviously spinning a fair bit."
The Proteas did themselves few favours in their bid to set a target of 200 on Thursday afternoon.
Vice-captain Aiden Markram drove Starc (2-29) straight to mid-off on two in the third over of the innings.
David Bedingham then top-edged a short Josh Hazlewood ball to deep backward square leg on 11, after being one of three men out hooking in the first innings.
And captain Temba Bavuma inexplicably swung hard across the line against Lyon with five minutes to go before stumps, and was bowled by a big-spinning offbreak.
Amid all that, Starc produced again after his first-innings 6-72, with a brute of a ball breaking a 64-run stand between Marques Ackerman and Bavuma.
The left-armer had a bouncer follow Ackerman as he tried to uppercut on 62, taking his bat edge and helmet on the way through to the slips.
A stunned Ackerman eventually tried to review, but was told by umpires and a vocal Travis Head that he'd run out of time before replays showed he had hit it anyway.
Pat Cummins again went 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 his counterpart 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 had lost 3-10 on Thursday.
Those extra runs could prove crucial, with Australia choosing at the toss to bat last in this contest.
