The Blues returned to Brunton Park for the visit of Oxford United in League One.
And manager Paul Simpson made five changes from the side that lost at Exeter City last time out - with those switches seeing Harry Lewis handed a debut in goal.
Dan Butterworth and Alfie McCalmont's cameo showings in Devon enough to see them handed starts, while Owen Moxon returned from injury to start in midfield.
There was also a first league start since August for academy graduate Jack Ellis on the right flank, with Josh Emmanuel, Sean Maguire, Taylor Charters, Jordan Gibson and Gabe Breeze the players replaced in the starting line-up.
Luke Armstrong and Harrison Neal also made their Brunton Park bows after starting at Exeter, and it was the latter who had the first shot of the afternoon - firing into the gloves of Oxford stopper Jamie Cumming from 25 yards after winning back possession.
The Blues were lively in the opening exchanges and a fine pass from Jack Robinson set Butterworth away down the left with the forward cleverly winning a corner. Moxon's teasing delivery was cleared as far as Butterworth who blazed over from 20 yards.
Neal and Corey Whelan then combined to allow the defender to over-lap into the box and his cut-back found Armstrong, whose attempted finish was repelled by Cumming.
And the January signing had the next sight of goal too, but his strike from the edge of the area was blocked after the referee had played advantage following a foul on Butterworth.
At the other end, Lewis was called into action just after the half hour mark as the stopper sprung to his right to tip Mark Harris' drive wide.
But from the resultant corner, the U's took the lead - Elliot Moore heading back across goal for Harris to hook home from close range.
That buoyed the visitors and Lewis had to parry a Tyler Goodrham effort from 25 yards as they enjoyed a spell of dominance.
United weren't deterred though, and finished the half strongly. McCalmont connected well with a shot with the outside of his foot but Cumming got behind it to hold, before the midfielder saw another strike deflected agonisingly wide after Neal's persistence allowed him to cross.
Oxford, however, would double their lead just two minutes into the second half. Harris found himself through on goal despite vociferous offside appeals, and squeezed the ball home off the upright.
The Cumbrians continued to look for a route back into the game and after being fed by Butterworth, Jon Mellish saw a shot held at the near post.
Lewis then showed his quick reactions to get down and keep out Cameron Brannagan's half-volley after the midfielder found space on the edge of the area before a third goal came just after the hour mark - Goodrham cutting in from the left and seeing his drilled strike nestle in the bottom corner.
United's fighting spirit wasn't knocked though, and they deservedly found the net through McCalmont on 71 minutes. Substitute Jordan Gibson's low strike was parried by Cumming and Armstrong did well to keep the ball alive before picking out McCalmont, whose low strike found the net.
Gibson then came close to reducing the deficit further when his cross was cleverly feignted by Joe Garner but flashed wide of the far post.
Garner himself then came agonisingly close after latching onto Gibson's set-back, but his goalbound effort from 10 yards was somehow kept out by a fine Cumming save.
The Blues continued to push into the seven minutes of injury time - Moxon coming closest with a near post drive into the arms of Cumming - but couldn't find a route back into the game as Oxford saw-out victory.
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Match Sponsor – Stanwix Holiday Park
Associate Sponsor – Motus Commercials Solway
Match Ball Sponsor – Fantails
Match Ball Sponsor – Tynedale Farm Services
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Goals
Carlisle United - McCalmont (71)
Oxford United - Harris (39, 47), Goodrham (67)
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Bookings
Carlisle United - Moxon (27), Neal (31), Mellish (43), Garner (72)
Oxford United - Bennett (53), Smyth (72)
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Teams
Carlisle United - Lewis, Moxon, Lavelle, McCalmont (Edmondson 87), Butterworth (Gibson 62), Whelan (Garner 62), Ellis, Robinson, Mellish, Neal (Charters 62), Armstrong. Subs: Breeze, Armer, Maguire.
Oxford United - Cumming, Brown, Moore, Brannagan, Harris, Bennett (Leigh 69), Smyth, Stevens, McGuane, Goodrham, Rodrigues. Subs: Eastwood, Thorniley, McEachran, Burey, Henry, O'Donkor.
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Match officials
Referee - Jacob Miles
Assistant Referee 1 - Daniel Woodward
Assistant Referee 2 - Emmanuel Edet
Fourth Official - Simon Clayton
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Attendance – 7,827 (562 away)