Rovers avenged last season's 4-1 defeat at Sixfields in style, as they ended a three-match losing run.
Ray Mathias' men went goal crazy, bagging three in a ten minute spell in the second half to dash the home side's hopes of a recovery.
Leading scorer Simon Haworth had put the visitors in front after ten minutes when he nIpped in ahead of Ian Sampson to stab an Iain Hume cross into the roof of the net.
Northampton almost replied immediately but a Chris Hargreaves shot went just wide while John Achterberg had to make diving saves from Jamie Forrester and Paul McGregor.
Rovers sounded a warning of what was to follow when Stuart Barlow raced clear seven minutes after the restart, only to be thwarted by Glyn Thompson in the home goal.
Thompson, on loan from Fulham was making his debut but soon found himself horribly exposed.
Haworth struck his eighth of the season in the 66th minute with a thumping right-foot shot from the edge of the box that gave Thompson no chance.
And five minutes later the goalkeeper could again only grasp air as Ryan Taylor executed a perfect 25-yard free kick inside the goalkeeper's right hand post.
Northampton's misery was completed in the 76th minute when substitute Alex Hay skipped clear and scored with a neat chip.
Northampton substitute Derek Asamoah briefly sparked hopes of a consolation only to be denied by the diving Achterberg.
This was only Tranmere's second visit to Sixfields and prior to last season's mauling, the previous League meeting had brought an identical 4-0 win to Tranmere at the County Ground back in March 1990.
The result hardly augurs well for the Cobblers ahead of their second round FA Cup replay back at Sixfields on Tuesday night against Cambridge.