Plymouth became only the second team to beat the Cobblers in 2015 with a 2-0 victory at Home Park in a game in which Northampton never got going.
Town were unable to implement their attacking strategy throughout a poor-quality contest in which the home side scored once in each half, through Anthony O’Connor and Lewis Alessandra.
It is only their second defeat since the turn of the year but does mean Northampton have slipped to five points adrift of the Sky Bet League Two play-offs.
Chris Wilder handed a full debut to James Gray, who signed on loan from Accrington the day before the game, while Darren Carter replaced the suspended Joel Byrom in central midfield and there was no place in the matchday squad for the ill Chris Hackett.
Also missing was leading goalscorer Marc Richards, who it has been confirmed will miss between six and eight weeks with a slight Achilles tear.
The game’s first major incident, though, came at the other end of the pitch, with Matt Duke inexplicably decided to catch a bouncing ball when a yard outside of his box.
Referee Stephen Martin gave the free-kick - he could hardly not - but did not produce a card of any colour for Duke, to the fury of the home supporters.
Lewis Alessandra should have added to his scoring sequence against the Cobblers when he was played clean through from Jason Taylor’s misjudged header in midfield on 26 minutes but his attempted lob was straight into Duke’s hands.
Moments later, though, the home side took the lead, Bobby Reid collecting the ball on the left wing and cutting it back for Anthony O’Connor to drive first time past Duke’s left hand and into the far corner.
The goal energised Plymouth, who started to play much more possession football, while Northampton looked jaded and struggled to get any momentum in their own game.
Plymouth regularly allowed the Cobblers to have the ball in attacking areas but for the large part they did little with it to hurt them.
Evan Horwood went close with curling free-kick on 70 minutes after Ivan Toney had been fouled inside the D and Billy Bodin manufactured a good shot in a tight area which was deflected over the bar with the goalkeeper beaten.
For the majority of the second half the home side had Northampton at an arm’s length and waited for them to over-commit themselves before grabbing a game-sealing second goal.
Drew Talbot broke down the inside-right channel on a counter-attack and passed square to the unmarked Alessandra, who stepped around Duke and rolled it into the empty net.
Plymouth: McCormick; Nelson, McHugh, Hartley; Mellor, B Reid, O’Connor, Talbot, Holmes-Dennis; R Reid, Alessandra
Subs: Blizzard (for McHugh 78), Brunt (for Reid 86), Banton (for Alessandra 88)
Not used: Bittner, Purrington, Cox, Banton, Harvey
Cobblers: Duke; Moloney, Cresswell, Collins, Horwood; Holmes; Taylor, Carter, D’Ath; Toney, Gray
Subs: Bodin (for D’Ath 61), O’Toole (for Gray 61)
Not used: Diamond, Newey, Clifton, Jalal
Away fans: 320
Referee: Stephen Martin