Carlisle United 1 Oxford United 3: Carlisle's relegation worries showed little sign of easing as promotion-chasing Oxford claimed the points at Brunton Park.
Alfie McCalmont's goal proved slim consolation as the Blues remained six points adrift of safety in the League One drop zone.
Mark Harris' double and a Tyler Goodrham strike meant new United keeper Harry Lewis suffered defeat on his debut.
McCalmont's first strike of the season gave slim hopes of a late fightback but back-to-back defeats leave the Cumbrians firmly in the mire.
Blues fans were upset with some key decisions by the officials regarding the first two Oxford goals but United could not summon enough in terms of a response against their fifth-placed visitors.
It unfolded in front of a 7,827 crowd as Carlisle remain 23rd in the table with just 19 games left to stage a dramatic revival to preserve their third-tier status.
Paul Simpson rang the changes after the previous weekend's defeat at Exeter City, making five alterations to his line-up.
Lewis went straight in for his debut while Owen Moxon returned from injury, as Simpson also handed starts to Jack Ellis, Dan Butterworth and McCalmont.
In Ellis's case it was only a second appearance of the league season as Josh Emmanuel dropped out of the squad, while dropping to the bench were Jordan Gibson, Taylor Charters, Sean Maguire and Gabe Breeze.
There were home debuts too for Luke Armstrong and Harrison Neal.
Oxford boss Des Buckingham handed a debut to new keeper Jamie Cumming and also recalled Goodrham and fit-again Elliott Moore in three changes to their previous weekend line-up.
Another new signing, Tyler Burey, was on the bench for the U's.
But it was second-bottom Carlisle who made the brighter start and forced most of the early opportunities.
Butterworth almost opened the visitors up with a positive dribble in the seventh minute, before Neal's cross was just too testing for the arriving Jack Robinson.
Butterworth's next attempt was wayward but Carlisle's pressing was keen while Ellis, Corey Whelan and Neal combined brightly on the right at times.
Oxford almost opened something up on the break but Ruben Rodrigues couldn't sufficiently control a well-aimed Cameron Brannagan ball over the defence.
It left keeper Lewis with little to do in terms of saves and Carlisle went on the attack again, Whelan finding space amid a neat move to cross for Armstrong, whose first-time finish was saved by Cumming.
Minutes later ref Jacob Miles played an advantage after Butterworth was fouled, but Armstrong's shot was blocked by the Oxford defence.
The visitors were so far making little impression in United's half, while Moxon and Neal both entered Miles' notebook for late midfield challenges.
Rodrigues sliced a Harris pass into the Warwick Road End as Oxford looked for an opening, and the visitors then found their way to an opener.
First, Harris's shot from the right went just wide but the officials awarded a corner, to Carlisle's disagreement.
Brannagan's delivery then caused problems in the United box and Harris pounced to send his finish high past Lewis from close range.
That deflated Carlisle and Oxford could have increased their lead had Harris and Fin Stevens not tried to attack the same Joe Bennett cross.
Lewis saved solidly from Goodrham while Butterworth was flagged offside as he ran clean through at the other end.
Mellish became the third Carlisle player booked as the half ended frustratingly, United twice denied an equaliser as McCalmont's volley failed to trouble Cumming and then, moments later, the midfielder came closer, seeing a low finish deflect just wide after Neal had ambushed Brannagan.
Blues fans gave ref Miles plenty of stick as the officials left the pitch for the break, United once more seeking a way back in order to give their survival fight the boost it desperately needed.
But things got immediately worse for the Cumbrians as, two minutes after the restart, they went further behind.
There was fury among home fans as assistant referee Emmanuel Edet's flag stayed down as Harris broke through on goal.
He rounded Lewis and eventually fired home off the post, as Carlisle supporters raged at the officials.
United now had it all to do, Mellish - pushed forward into midfield - struggling to test Cumming as he overlapped onto a chance in the Oxford box.
Brannagan was denied by a strong Lewis save before Simpson made a triple change, introducing Gibson, Charters and Joe Garner.
But Oxford soon killed things as Goodrham cut into space on the left and sent an impressive low finish across Lewis and into the bottom corner.
That was the cue for a number of home fans to leave after just 68 minutes of the game.
Carlisle replied soon after as they kept things alive after Cumming's save from Gibson, the ball eventually worked to McCalmont who drove home his first goal of the season from the middle of the box.
Garner was then involved in a skirmish with defenders after a challenge on the visiting keeper, the sub and Oxford's Oisin Smyth both booked.
Gibson's next delivery bounced just wide but it remained a long shot for Carlisle to salvage anything.
Cumming denied Garner a likely goal with a valiant save on the line after good work by Gibson five minutes from time, before Simpson sent on Ryan Edmondson for the closing stages.
But Carlisle couldn't create anything bar an injury-time free-kick which Robinson blazed into the Warwick Road End - and their struggles showed no sign of easing.
United: Lewis, Ellis, Robinson, Lavelle, Mellish, Whelan (Garner 62), Neal (Charters 62), Moxon, McCalmont (Edmondson 86), Butterworth (Gibson 62), Armstrong. Not used: Breeze, Armer, Maguire.
Goal: McCalmont 71.
Booked: Moxon, Neal, Mellish, Garner.
Oxford: Cumming, Brown, Moore, Bennett (Leigh 69), Stevens, Smyth, Brannagan, McGuane, Goodrham, Rodrigues, Harris. Not used: Eastwood, Thorniley, McEachran, Burey, Henry, O’Donkor.
Goals: Harris 39, 47, Goodrham 68.
Booked: Bennett, Smyth.
Ref: Jacob Miles.
Crowd: 7,827 (562 Oxford fans).
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