The Cobblers have now failed to beat Southend United in their last ten attempts and this disappointment left them still locked in the final relegation place, although three of their five remaining matches are at home.
Southend were a goal ahead at the break, courtesy of a 38th minute header by Jean-Francois Christophe, who was returning to the side as the only change from the 2-0 home defeat by MK Dons on Good Friday.
Christophe rose decisively to head in a corner from Franck Moussa, which brightened up a stale first half.
The home side were level five minutes after the break when a Danny Jackman cross eventually fell to the feet of Adebayo Akinfenwa and the striker had time to fire home his 14th goal of the season.
Akinfenwa then headed wide from a good opening, but Southend then scored twice within a five-minute spell to grab a matchwinning lead.
Firstly, Theo Robinson ran on to a pass from Damien Scannell and rammed home a low shot which beat Chris Dunn inside his left-hand post.
Then former Northampton player Lee Barnard was sent clear by a clever lob from Alan McCormack and he jinked his way past a defender and Dunn, before poking the ball into an empty net.
Jackman almost reduced the arrears in the 67th minute with a brilliant free-kick which Steve Mildenhall tipped over the crossbar in acrobatic fashion, while at the other end Dunn denied McCormack.
Northampton grabbed themselves a lifeline with ten minutes to go when substitute Aleksander Prijovic rammed home a loose ball in the box after the Southend defence failed to deal with a long throw by Andy Holt.
There was still time for Robinson to fire narrowly wide for Southend, while an injury time free-kick from Jackman also missed the target.