The O's, who had beaten Premiership side Fulham in the FA Cup a week earlier, were second best throughout to a Northampton side who deserved their win with a goal in each half from Scott McGleish and Chris Doig.
The win pushed the Cobblers up into fifth place and kept alive their hopes of a top-three finish.
The visitors were quick out of the blocks and Jason Lee, signed from Boston, proved to be a real handful for the home defence.
Lee sent a 10th minute header just wide before Orient slowly found some resemblance of form and Jabo Ibehre looked to have put them ahead on 14 minutes but his effort was ruled out for a foul on Luke Chambers.
As O's enjoyed their best spell top scorer Gary Alexander fired a shot wide from 14 yards.
But Northampton hit back and former Orient striker McGleish had a goal ruled out for an illegal challenge on the home goal keeper Glyn Garner which earned him a booking.
But it was McLeish who struck on 35 minutes when he fired home from a tight angle after Garner had fumbled Lee's shot.
Garner's misery continued in the second half when he had to leave the field following a collision with Gaby Zakauni and Lee which left him momentarily unconscious and he was replaced by Glenn Morris.
But Morris was quickly picking the ball out of the net when Doig headed home David Hunt's corner from close range.
Orient pulled a goal back on 86 minutes when Daryl McMahon fired in an effort from 18 yards after Michael Simpson and Lee Steele had gone close.
Despite seven minutes of stoppage time Orient failed to grab a leveller - although Alexander missed a great chance but it was Town who looked dangerous on the break with McGleish and Hunt both going close to stretching their advantage.