Joe Root was 60 not out and Nick Compton made 49 as England reached 172 for 3 in its second innings, well ahead in the series opener with seven wickets left and two days to play.
England's dominant position in Durban started with four wickets each for quick bowler Stuart Broad and spinner Moeen Ali to dismiss top-ranked South Africa for 214 in its first innings.
"We're pretty calm. We're not getting overexcited," Ali said.
South Africa's predicament was made worse by a right shoulder injury for its frontline fast bowler Dale Steyn, which could have repercussions for the rest of the four-match series. South Africa's team manager said it would only be decided on Tuesday morning if Steyn can bowl again in the match and he's a doubt for the second test in Cape Town starting on Saturday.
Compton again frustrated South Africa after a marathon 85 in England's first-innings total of 303. And after missing out earlier in the test, Root stroked four fours and a six and was well-set, making 50 or more for the 13th time in 26 innings this year.
The partnership of 71 between Root and Compton late in the day further sapped South Africa's morale, after both men were dropped early in their innings. Compton survived a simple chance to Dean Elgar at second slip on 11 and Root a more difficult high catch that wicketkeeper AB de Villiers made a mess of when the batsman was on six. Compton was missed again on 45 by a diving De Villiers before falling two balls later.
Damage had already been done.
Victory in Durban, which appears likely, would give England a major boost in its pursuit of a first series victory in South Africa for over 10 years.
South Africa's Dean Elgar celebrates his century. (AP)
South Africa, coming off a comprehensive 3-0 series loss in India, was facing more questions about its ranking as the best test team in the world. The Proteas' first-innings flop meant the No. 1 team has failed to make 300 in its last 11 test innings.
Opener Elgar made 118 not out and batted all the way through to hold up the faltering innings, but that didn't disguise the current struggles of the South Africa lineup. It was the first century by a South African in seven tests.
"It's obviously something we're talking about in the change room," Elgar said. "We do have a new batting lineup and sometimes it takes time to find your feet."
South Africa now had to "show some character and some fight," Elgar said, to scrap for a draw.
South Africa's batting fragility aside, Broad was still especially impressive in the absence of the injured James Anderson to put England on top.
"I don't think South Africa played that poorly," Ali said, "I just thought we bowled really well."
At the start of the day, Broad rattled Temba Bavuma's stumps with the second ball of play to again set the tone after his three vital wickets swung momentum England's way late on Sunday.
Monday was England's day from start to finish.
England's bowlers conceded just 77 more runs in taking the last six South African first-innings wickets. Ali's influence was also a major plus for England as he spun out the middle order. South Africa will have to bat to save the game on a deteriorating Durban pitch that the spinner will likely take advantage of.
"Yeah, it's going to be more of exactly the same," Ali said. "Try to bowl tight and hopefully the wickets will come."
South Africa's attack toiled when England batted again but was significantly blunted by the absence of top-ranked test bowler Steyn.
The quick bowler had slumped over clutching his right shoulder and bowling arm early in England's second innings, and left for treatment without completing his over. He returned some time later, tried to bowl again, and again trudged off midway through the over.
South Africa team manager Mohammed Moosajee said an "inconclusive" scan had shown no muscle or ligament damage and South Africa would wait to see how their star came through the warmup on Tuesday. Steyn, who experienced discomfort since the first day of the match, would have further tests after the game to see if he can play in Cape Town.
Brief Scores (for FULL SCORECARD click here)
England 1st innings: 303 all out in 100.1 overs (Nick Compton 85, James Taylor 70; Dale Steyn 4-70, Morne Morkel 4-76).
South Africa 1st innings: 214 all out in 81.4 overs (Dean Elgar 118 not out, AB de Villiers 49; Stuart Broad 4-25, Moeen Ali 4-69).
England 2nd innings: 172 for 3 after 64 overs (Joe Root 60 not out, Nick Compton 49; Dane Piedt 2-65).