Luke Guttridge scored against his former side, with little time left on the clock, bagging the goal which leapfrogs Wycombe Wanderers into the top spot.
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After a goalless first half, each side cancelled each other out as they swapped chances at opposite ends.
Guttridge replaced Alex Lawless as a second-half substitute and immediately caused problems for his former side.
The game appeared to be heading towards a stalemate but it was Guttridge's right footed shot that broke the game's deadlock and ultimately secured all three points and top spot in League Two.
The win was Luton's eighth in nine league games, with Northampton slipping down to 18th place, seven points above the drop.