A late goal by Plymouth defender Kelland Watts was the deciding factor as Northampton were beaten 2-1 in Devon.
The game was level in the final stages after Ricky Korboa cancelled out Frank Nouble’s first half opener.
But with 4 minutes to play, Newcastle loanee Watts turned the ball in at a corner to decide the contest in the Pilgrims’ favour.
The result means Northampton make the long trip back east on the back of defeat in the battle of two sides promoted from last season’s curtailed League 2 campaign, while they also sit in the relegation zone after the opening 6 games.
Northampton did enjoy chances in the opening half, with Sam Hoskins and Danny Rose coming particularly close.
George Cooper and Danny Mayor had come close with errant opportunities for Plymouth in the opening stages, but they would break through with 4 minutes remaining of the first half.
Nouble would score the goal that did so, with the striker turning in Conor Grant’s cross.
George Cooper would then be denied by Steve Arnold as Plymouth threatened a second straight after the break.
Having made it past that, Northampton grew into the game and equalised just after the hour, as Korboa received Hoskins’ pass and beat home goalkeeper Michael Cooper.
Michael Harriman then found the side netting moments after that, in Northampton’s closest chance to pull off the comeback.
But instead, Plymouth would strike the game’s third goal in the final minutes, when Watts volleyed in at a corner, and Northampton were unable to recover a second time as the home side took the rewards.