Pace bowlers Morne Morkel and Dale Steyn claimed four wickets apiece to help dismiss England for 203 on the first day of the second Test at Headingley on Friday.
Morkel took four for 52 and Steyn four for 76 before the home team hit back in the final session to reduce the Proteas to 101 for three at the close.
Andrew Flintoff, in the thick of the action on his Test comeback after 18 months, took a catch and a wicket.
Hashim Amla (18) and Ashwell Prince (9) were the not out batsman as South Africa trailed England by 102 runs.
The first match in the four-Test series at Lord's was drawn.
Amla was almost the fourth man out when his leading edge was caught by a diving Michael Vaughan at mid-off off Flintoff. But after reaching the end of his walk back to the pavilion he was instructed by captain Graeme Smith to wait for the third umpire's decision which gave him a reprieve.
It was the second such instance after South Africa's AB de Villiers earlier claimed a catch at third slip off the bat of Andrew Strauss. Replays showed the ball had clearly been grounded.
The South African bowlers vindicated Smith's decision to bowl first in dull and humid conditions after he admitted he wrongly chose to bowl first at Lord's. England were 70 for three at lunch and all out by tea.
England started confidently by reaching 26 for no loss before Alastair Cook was given out caught down the leg side off Morkel for 18 by umpire Billy Bowden, even though replays clearly showed the ball brushing his trouser leg.
Kevin Pietersen top scored for England with an exhilarating 45 off 46 balls. He was threatening the tourists with some majestic stroke-play, in particular a drive through extra-cover for four off the back foot from Steyn, the ball before he was dismissed.
Pietersen, attempting another boundary, edged the ball to Smith at first slip.
The most interesting sequence of the afternoon session came with the arrival of former skipper Flintoff, who came to the crease at number seven with the score on 123 for five.
He was unable to stop the slide, lasting 28 deliveries and striking four boundaries in his 17.
South Africa were given a solid start of 51 by Smith and Neil McKenzie, before the latter edged James Anderson to Flintoff at second slip and was out for 15. Smith's innings of 44 was ended by Flintoff, whose short-pitched ball was caught by Strauss at first slip. Anderson then bowled Jacques Kallis for four, bottom edging a short ball angled into him.
Earlier, England gave a debut to swing bowler Darren Pattinson after Ryan Sidebottom failed a fitness test. Flintoff came in for Paul Collingwood.