Winger Sam Aiston provided the inspiration as Tranmere recorded their second League One victory of the week.
The Merseysiders were rocked by an opening goal from Chesterfield on the half hour but their response was terrific to lead 3-1 by the interval and they cruised through the second half.
Jamie O'Hara put the visitors in front on the half hour with a superb 35-yard volley which left keeper Dino Seremet rooted to the spot.
Tranmere were level by the 36th minute with Aiston stabbing the ball home at the far post from a pass by Jason McAteer.
Aiston then produced a terrific volley from the corner of the box in the 39th minute after Calvin Zola flicked on a clearance by Seremet.
The third goal came in first-half injury-time. It was an easy tap-in for Chris Greenacre with visiting keeper Carl Muggleton unable to hold a hard shot by Zola.
Chesterfield tried hard to get back into the picture but it was all over for them in the 65th minute.
Steve O'Leary blasted into the roof of the net from close range when set up by Zola.
It then needed a fine finger-tip save by Muggleton to keep out a 72nd minute header by substitute Delroy Facey.
Chesterfield finished well but could not find a way through with Adam Smith volleying over and Aaron Downes also missing the target following an O'Hara free-kick.
