A brace from Adebayo Akinfenwa helped Northampton to extend Wycombe's winless league run to six games.
Charles Dunne hit a post for Wanderers, but Akinfenwa headed in Chris Hackett's cross to put the Cobblers ahead.
Akinfenwa netted his 11th league goal of the season from the spot after Dave Winfield tripped Clive Platt and Hackett scored a third on the break.
Joel Grant scored a consolation from the spot, before Akinfenwa was denied a hat-trick by the woodwork late on.
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Northampton Town manager Aidy Boothroyd told BBC Radio Northampton:
"It was a really good first half performance. But I thought there were a lot of mentally tired players out there at the end. You've got to be able to dig in, and I thought we did that.
"I thought Ben Harding was outstanding and unlucky not to get man of the match. Lewis Hornby is doing the ugly things very well and he's picking good passes.
"Ishmel Demontagnac told me he was disappointed to be taken off, and I don't mind that. He's accepted it, we're fine.
"Adebayo Akinfenwa can't stop scoring and I'm delighted. When he plays like that, he's unplayable."