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The injury-hit U's have now gone nine games without a victory in League Two after they were beaten by the Cobblers, who had started the game second-bottom in the division.
Goals from Matty Warhurst and Sam Hoskins secured victory for the hosts on a day when little went right for Colchester at a soggy Sixfields, whose flat, lethargic performance lacked quality and any real spark in front of their 600 fans.
Colchester boss Danny Cowley, who watched from the stands due to a touchline ban, made three changes to his starting line-up for their game at Northampton.
Ben Perry returned to the starting line-up for the first time in the league since August against his former club, while Beryly Lubala and Oscar Thorn also returned to the U’s team.
Paul Digby, Kane Vincent-Young and Jaden Williams dropped to the bench, while Jack Payne was also among the substitutes following his recent ankle injury.
Northampton, watched by Alexandre Pato and the SAC group who have just taken over at Sixfields and had been in talks about a U's takeover, started well with Rob Hunt having to clear away from near his own goal-line in the opening minutes after Owen Dale had whipped a ball into the U’s box.
And Colchester fell behind in the ninth minute, with Matty Warhurst sending a powerful header past U’s keeper Thimothee Lo-Tutala from Connor Evans’ excellent cross into the box.
The U’s looked for a response and it almost came in the 15th minute when Perry’s first-time low shot was saved by Northampton goalkeeper Zach Jeacock, after Thorn had done well to create the chance.
Lee Evans fired a shot over from just outside the area for the Cobblers but Colchester came close to an equaliser five minutes before half-time when Ihionvien headed a good opportunity wide at the far post, after Moses Sesay had curled a delivery into a congested area.
The U's received a let-off just before half-time when a breakdown in communication resulted in Ellis Iandolo inadvertently nodding the ball towards his own goal on the edge of the penalty area, with Lo-Tutala doing well to recover and palm the ball away from the lurking Joe Wormleighton.
Balance - Colchester United's Beryly Lubala in action at Northampton Town (Image: Richard Blaxall)
But the U's went in at the break behind and requiring a big second-half performance, to get themselves back in the contest.
Jaden Williams was sent on for Ihionvien five minutes after the interval but seconds later, Colchester fell further behind.
Sam Hoskins converted neatly first time from close range, after Owen Dale had delivered a cross into the U's six-yard box.
It left Colchester with a mountain to climb and it was almost 3-0 in the 56th minute when Connor Evans' low strike struck the foot of a post before coming back into play.
Payne and Vincent-Young were sent on by the U's on the hour mark in a bid to try and get back in the game but Northampton went close again midway through the second half when Perry was forced to glance away from near his own goal-line, after a corner had been flicked dangerously towards goal by the hosts.
Battle - Colchester United's Ellis Iandolo in action against Northampton Town (Image: Richard Blaxall)
Northampton went close again when Dale raced through on goal and Lo-Tutala did well to smother the ball at the Northampton player's feet.
And seconds later, Lo-Tutala had to get down low to push away substitute Elliott List's strike for a corner, as Colchester tumbled to defeat.
MATCH STATS: COLCHESTER UNITED: Lo-Tutala, Hunt (sub Vincent-Young, 62), Tucker, Terry, Iandolo, Jay Williams (sub Payne, 62), Perry (sub Digby, 73), Thorn, Sesay, Lubala (sub Connolly, 73), Ihionvien (sub Jaden Williams, 50).
Substitutes (not used): Kuffour Jnr, Raggett.
Northampton Town: Jeacock, Maxwell (sub Powell, 67), Guthrie, Moore, Wormleighton, Dale (sub Fornah, 90), Evans, Donacien, Evans, Warhurst (sub List, 82), Hoskins (sub O'Brien-Whitmarsh, 67).
Substitutes (not used): Briggs, Dadge, Dyche.
Referee: Scott Jackson.
Goals: Northampton: Warhurst (9), Hoskins (50).
Bookings: Northampton: Hoskins (foul, 15), Evans (unsporting behaviour, 32). Colchester: Sesay (unsporting behaviour, 30).
Sending off: None.
Attendance: 5,959 (601 U's fans).