Gary McDonald gave the Shrimps the lead in first-half injury-time at the Globe Arena.
Richard Brodie delivered a cross from the left byline and McDonald sneaked in behind his marker at the far post to volley past Richard O'Donnell from six yards out.
Brodie was the provider again for the second goal after 52 minutes. Again he got the better of Terrell Forbes to provide the perfect chance for Lewis Alessandra to volley past O'Donnell from close range.
Chesterfield started the game brightly with Craig Westcarr stabbing an early effort just wide of the left-hand post after the ball broke free in the Morecambe box.
And the same player forced Barry Roche, a former Spireites, into a neat save after a slip from defender Robbie Threlfall gave him a free run on goal.
The Spireites, who arrived in Lancashire on an eight-game unbeaten league run, also should have scored after 16 minutes when Neal Trotman had a free header from a Westcarr corner. However, the defender missed the target with his effort by quite some margin.