Paul Borrington top scored with 75 – but quick wickets with the second new ball helped Durham fightback on Day Two at the County Ground.
Borrington hit eight fours during his patient innings - during which he shared a 106-run stand with Shivnarine Chanderpaul (53) to move the hosts onto 206-2 shortly after lunch.
But Chris Rushworth (5-47) and Graham Onions (4-62) tore through the Derbyshire middle-order with the new ball, claiming the last seven wickets for just 56 runs to dismiss the hosts for 298.
Tony Palladino (2-19), however, responded with two late wickets to leave the match finely poised with Durham 82-2, trailing by 216 runs.
Resuming on 99-1, Derbyshire lost Captain Wayne Madsen (32) in the first over of the day – but a stubborn stand between Borrington and Chanderpaul helped the hosts recover from 100-2 to 206-2.
Chanderpaul completed his sixth half-century of the campaign at the start of the afternoon session. His 128-ball vigil featured five fours, before he was finally removed by Usman Arshad for 53.
New man Richard Johnson brought some much needed impetus to the innings, as the right-handed batsman bludgeoned three fours and a six in his brisk 29.
But Johnson was one of four wickets to fall inside four overs to the second new ball.
It took just 10 balls for the first to fall as Borrington’s fine innings finally came to an end. The 25-year-old batted for over five hours, hitting eight fours, to top score with 75 before he was caught at slip off Onions.
Alex Hughes (2) also fell to the England seamer, after Chris Rushworth had removed Tom Poynton (0) to leave the hosts on 248-7.
Tony Palladino and David Wainwright, however, stemmed the flow of wickets to add 29 runs before tea - but both fell in quick session after the restart as Derbyshire were all out for 298.
With 20 overs still remaining, Durham made a quick start to their reply as Mark Stoneman raced to 30 as part of a 49-run opening stand.
It was Palladino who prized the important opening breakthrough, removing Stoneman in the 12th over.
And the 30-year-old paceman soon claimed a second, clean bowling Keaton Jennings (16) to help peg Durham back to 82-2 at stumps - with Scott Borthwick and Will Smith unbeaten on 21 and three respectively.
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