Clarke Carlisle and Barry Nicholson struck a goal in each half to secure Preston their first win of the season and leave Chesterfield chasing their first victory.
It was Preston's first win in npower League One and although Chesterfield had their moments, Phil Brown's team were good value for the three points.
Chesterfield had conceeded from a set piece on Saturday and were caught cold again when Carlisle headed in a 17th-minute corner.
Jamie Proctor was close to a second four minutes later with a low drive that Tommy Lee parried, but Chesterfield almost equalised on the half-hour when Dean Morgan's goalbound shot struck a defender.
Iain Hume and Proctor fired wide at the start of the second half, but Chesterfield went close when a poor punch by Iain Turner allowed Mark Allott to shoot just past the post.
But Preston tightened their grip on the match in the 70th minute when Brian McLean crossed from the right and Nicholson stole in to loop a downward header over Lee in front of the 960 travelling fans.
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