Wycombe caretaker boss Gareth Ainsworth admitted the defeat to Oxford had dealt a blow to his hopes of getting the job.
Tom Craddock set up the first for James Constable before the U's striker grabbed one for himself - firing home his fifth in three games at the start of the second half.
Joel Grant instantly pulled one back from the penalty spot but Johnny Mullins headed in a third for Oxford for their first league win on the road since August.
Wycombe co-chairman Don Woodward admitted before the match the job would be Ainsworth's if he kept their recent good run going but the interim player-boss accepted the performance against Oxford had done him few favours.
"It's probably a bit of a whack on my CV, but we'll try and turn it round," he said. "Losing one in six up to today has been very good and we'd been playing very well and defending very well - we were confident going into this. It's a dent but there's no news on a managerial decision.
"We didn't really start playing until 30 minutes in. We started playing well but losing another sloppy goal two minutes into the second half was killer. We got one back but it was always an uphill struggle."