The Chairboys' 4-1 victory left the Cobblers at the foot of the Football League and it proved to be enough for chairman David Cardoza to make a decisive decision and the former Watford boss departed less than an hour after the final whistle.
A statement from the club read: "Aidy Boothroyd has left Northampton Town Football Club.
"The decision was made by Chairman David Cardoza after Saturday's loss to Wycombe Wanderers.
"The club will make no further comment at this time, but will provide a further update on Monday."
Wycombe manager Gareth Ainsworth was delighted to see his side finally get back to winning ways at Sixfields.
Ainsworth said: "We didn't have the best preparation for the game, losing a couple of players on Friday but in adversity they showed great character.
"The players were really up for the game. The conditions were difficult but we showed we can battle as well as play football.
"Baring 10 minutes at the start of the second half I thought we controlled the game and were worthy winners.
"It's been a long time coming for the players, staff and supporters but we've stuck together, kept believing and knew something good was around the corner.
"Joe Kuffour has been waiting patiently for his chance, he's not played many games, but he led the line brilliantly with Dean Morgan and the rest of the players followed their example.
"He showed me in training that Joe Kuffour was back to his best and he was fantastic for me.
"And what a time for Stuart [Lewis] to score. It was a nervy time for us before he scored our third goal. He's a great character and he came up to me at the end and said 'that one was for you gaffer'.
"It's a great start to the festive period but now we've got to take this into our next games."