The Merseysiders tipped the balance with three goals in 11 minutes before the break and added a fourth in injury time.
The visitors were not helped by the loss of goalscorer Ryan Gilligan after 36 minutes and skipper Chris Doig at half-time.
Northampton went ahead in the tenth minute. Gilligan capitalised on a dreadful back-pass by Ian Goodison to net with an angled effort.
Little went right for Tranmere for half-an-hour, but a flowing attack in the 35th minute saw Steve Jennings set up Bas Savage for the equaliser.
Three minutes later, Antony Kay struck from just outside the box following a part-clearance with the ball taking a deflection out of the reach of keeper Chris Dunn.
Tranmere scored again in the 45th minute. Craig Curren blasted home from close-range after a Kay header from a Chris Shuker corner was turned on to the bar by Dunn.
The Cobblers at the time were down to ten men, with Doig off, being treated for a head injury.
The second half was something of an anti-climax. Andy Holt headed wide for Northampton, but it was the nearest they came to a second goal.
Tranmere put the icing on the cake two minutes into added time with substitute Chris Greenacre setting-up 71st-minute replacement Ian Moore for an easy fourth.
Kay and Savage were outstanding for the Merseysiders, who gained in confidence as the game progressed.
Danny Jackman shone for the Cobblers, but the Carling Cup heroes always seemed to be fighting a losing battle once Tranmere found their rhythm.