Flintoff, back in the team at the expense of Paul Collingwood, following ankle and side injuries, had made 17 when he flat-footedly edged Dale Steyn through to wicket-keeper Mark Boucher.
But it was Morne Morkel, with four wickets for 52 runs in 15 overs, who led the way as the much-vaunted South Africa pace attack, who had been disappointing in the drawn first Test at Lord's, lived up to their billing albeit in helpful, overcast conditions.
Fellow quick Steyn was not far behind with four for 76.
Several of the top-order made starts with only captain Michael Vaughan, out for nought, falling in single figures.
Kevin Pietersen's 45 was the top score.
England, who were 186 for nine, did have the consolation of getting past 200 before No 11 Darren Pattinson, handed a surprise Test debut, was last man out for eight as Boucher held his fifth catch of the innings.
England resumed after lunch on 70 for three.
South Africa-born Pietersen, who made a century at Lord's, was 17 not out and Ian Bell, whose 199 in the series opener was his Test-best score, was unbeaten on four.
Pietersen came out all guns blazing, driving Steyn off the backfoot for four through the covers.
But five runs short of a fifty he tried to drive Steyn without moving his feet and edged to South Africa captain Graeme Smith at first slip.
Wicket-keeper Tim Ambrose, promoted to No 6 didn't linger long before, on 12, he played at a Makhaya Ntini ball angled across him, from round the wicket, and edged to Boucher.
Flintoff's first scoring shot was a streaky cut through the gap between slips and fully, off Ntini.
However, his second four, off Morkel, was much more authoritative with Flintoff going back and across before punching the ball off the backfoot.
Bell had looked in good touch but, on 31, he was bowled off the inside edge driving at all-rounder Jacques Kallis.
Left-handed openers Andrew Strauss and Alastair Cook made a steady start.
But South Africa had a breakthrough when Cook was given out for 18 by umpire Billy Bowden, caught down the legside by Boucher off Morkel, when it appeared the ball had brushed the batsman's trousers and missed the edge of the bat.
However, there was no doubt at all when, nine balls later. Vaughan, who made just two at Lord's, edged a full-length Steyn delivery to Smith.
It was not the way Vaughan, on his Yorkshire home ground, would have wanted to mark his 50th Test as England captain.
Former roof tiler Pattinson, who has appeared in just 11 first-class matches, replaced fellow Nottinghamshire pace bowler Ryan Sidebottom after the left-arm quick was ruled out with a back strain.
Born in Grimsby, northern England, but raised in Australia, the 29-year-old only made his first-class debut, for state side Victoria, in January 2007 after several seasons playing for Melbourne club side Dandenong.
This is Pattinson's first season of county cricket and he has so far taken 29 first-class wickets in six matches at 20.86 apiece, figures which persuaded the selectors to pitch him in at Headingley.