Northampton dropped to the bottom of League Two after the 4-1 home defeat and Torquay United's 1-0 win over Dagenham and Redbridge.
Jo Kuffour and Kortney Hause scored in the first 14 minutes for Wycombe, and although Izale McLeod pulled a goal back just after half-time, Wycombe responded strongly to finish with a flurry.
Stuart Lewis and Dean Morgan netted late goals as Wycombe sealed their first league success in more than two months – prompting Northampton to act and dismiss manager Boothroyd.
A short statement on the club's official website 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."
Oxford missed the chance to move ahead of leaders Chesterfield after being held to a frustrating 0-0 draw at York City. York have not won a match since October.
Scunthorpe United's surge up the table continued as they extended their unbeaten run to five matches, of which four have been wins, with a 2-0 home success against Morecambe.
Deon Burton scored both goals for Scunthorpe, who are third in the table.
Fourth-placed Fleetwood Town were upset 2-0 at home by Cheltenham Town, with Troy Brown and Jermaine McGlashan getting on the scoresheet for the victors.
Bury are in the relegation zone after losing 2-1 at Plymouth Argyle – Reuben Reid struck the winner with 12 minutes to play.
Portsmouth's collapse continued, as their winless run extended to nine matches, of which seven have been defeats.
The 2008 FA Cup winners were beaten 2-0 at Bristol Rovers, who scored through Ollie Clarke and David Clarkson.
And Mansfield Town's wretched record also grew older – Accrington Stanley beat them 3-2 in a thrilling encounter.
Accrington Stanley trailed 2-1 in the fourth minute of stoppage time, but late goals from Kal Naismith and James Gray sealed an incredible win for James Beattie's side.
Mansfield have not won a league match since September.
Other results on Saturday saw Burton Albion's unbeaten run stretch to seven matches, as they drew 1-1 at Hartlepool United, while Aaron Downes' strike was enough for Torquay.
And Newport County's match with AFC Wimbledon was postponed after a pitch inspection at Rodney Parade.
