Goals by recalled striker Calvin Zola, Gareth Taylor and a penalty by John Mullin put Tranmere out of sight before the Cobblers' star man and skipper Scott McGleish grabbed a consolation with 16 minutes left.
For Northampton it was a fourth defeat from five home games this season, but it is a different story for Rovers who bounced back from Tuesday's defeat at Rotherham.
It could all have been different if McGleish's strike partner Andy Kirk had been on the same sort of form as his skipper.
After only 12 minutes a poor clearance by Gavin Ward allowed Kirk the chance to run on goal but he fired straight at the keeper.
Within two minutes the visitors were ahead when Zola was given time and space by Town's central defenders and the lively striker curled a right-foot shot inside Mark Bunn's left-hand post.
Tranmere made it 2-0 ten minutes before the break when Zola fed the industrious Chris Shuker and his cross was glanced in by the head of former Forest man Taylor.
Kirk lashed a shot on the turn over before the break but Tranmere could have turned round even further in front only for substitute Steve Davies to blast over.
Kirk had a brilliant chance to pull one back six minutes after the restart when a low cross by debut loan man Mitchell Cole found him only four yards from goal, but with the target yawning open, he somehow managed to scoop his shot over the bar.
Rovers all but wrapped up the points when referee Gary Sutton awarded a spot-kick for handball against substitute Brett Johnson as he challenged Taylor for a hanging cross by Davies.
Kirk did better in the 66th minute but his snapshot was punched away by Ward before Johnson went close by heading over a cross by David Hunt.
McGleish latched on to Hunt's pass to reduce the arrears and this prompted a passionate rally by the hosts but the closest they came was when Rovers skipper Ian Goodison cleared off the line brilliantly from Kirk's shot.