Two goals early in the second half pout them in the driving seat as Huddersfield's hopes of a top-six finish were severely dented.
An early mis-hit shot by Ian Craney was no trouble to home keeper Danny Coyne, but as play swung the other end visiting keeper Alex Smithies did well to keep out a power drive by Steve Jennings.
From the subsequent corner skipper Antony Kay was given all the room he needed to head home from the cross by Charlie Barnett on six minutes.
Huddersfield were slow to make an impact and had Michael Collins booked for a challenge on Danny Mayor on 20 minutes.
Three minutes later Collins provided the cross for Andy Booth to head an excellent equaliser, with Coyne having no chance.
Anthony Pilkington saw a shot blocked after good Town pressure just past the half-hour mark. Ten minutes later Coyne made a comfortable stop from a Robbie Williams free-kick.
Skipper Chris Lucketti collected the second yellow card of the day on 45 minutes for a foul on Bas Savage.
Ed Sonko replaced Terry Gornell in the Tranmere attack on the re-start and they regained the lead on 50 minutes with a great strike by Savage from just outside the corner of the box.
It became 3-1 three minutes later. An Andy Taylor free-kick was only part cleared and Kay blasted home from 12 yards to reach ten league goals for the season.
Kay was outstanding for the winners with good support from Jennings.
Pilkington and Lucketti tried hard for the losers, although Pilkington collected the third caution of the afternoon on 74 minutes for dissent.