Northampton paid the price for a poor first-half display as Colchester denied them a third straight win and claimed their own second win in five days.
Chris Coyne should have put the visitors in front before Clive Platt did, heading in Dean Hammond's cross.
Three minutes later former Northampton player Paul Reid made it 2-0 with a header from Johnnie Jackson's corner.
Danny Jackman's deflected free-kick in the second half gave the home side hope but they failed to find an equaliser.
Northampton: Fielding, Kyle Walker (Bignall 46), Crowe, Todd, Jackman, Guttridge, Coke, Gilligan (Holt 61), Davis, McGleish (Henderson 71), Constantine. Subs Not Used: Dunn, Hughes.
Booked: Guttridge, Coke.
Goals: Jackman 53.
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Booked: Baldwin, Platt, Easter.
Goals: Platt 23, Reid 26.
Att: 4,833
Ref: Karl Evans (Greater Manchester).
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