Boothroyd, who had come under pressure after his 2012 play-off finalists spent most of this season languishing in the relegation zone, had only this week thanked chairman David Cardoza for giving him time to turn things around.
But the heavy defeat to the Chairboys was the last straw, with the former Watford boss relieved of his duties with immediate effect.
"The board of directors just felt the time was right for a change," Northampton head of media Gareth Willsher told the BBC.
"He was a manager we all respected and it is disappointing it has come to this."
Matt Bloomfield forced Duke to palm his low drive around the post and Dean Morgan had a header ruled out for offside from another Arnold cross.
In between, Stuart Dallas went close with a shot on the turn for the shell-shocked Cobblers. But Wycombe doubled their lead in the 13th minute when Max Kretzschmar's deep cross was headed back across goal by Morgan for centre-back Kortney Hause to head home.
Duke thwarted Kuffour after he broke through before the Cobblers finally created a couple of chances. Mathias Kouo-Doumbe put Chris Hackett's cross over from six yards and Izale McLeod tested Matt Ingram with a fierce drive but then wasted a great chance when he fired over from a good position.
Substitute Luke Norris went close after the restart when his overhead kick flew past the post. But the Cobblers reduced the arrears in the 51st minute when Norris headed down Hackett's cross for McLeod to get the final touch.
Northampton had to play with 10 men after Kouo-Doumbe limped off midway through the second half. And the Chairboys took advantage. Skipper Stuart Lewis made the points safe in the 79th minute when he shot home through a crowded box from 15 yards and Morgan raced clear to round it off in the 85th minute.
- Sports & Recreation
- David Cardoza
- Dean Morgan
- Nick Arnold