The visitors raced into a three-goal lead inside 15 minutes and hung on at the end – but how Town will be left ruing that appalling start.
Stephen Crainey made three changes to the side that fell to Accrington the previous weekend.
Kieran O’Hara replaced the suspended Alex Cairns in goal, while Cian Hayes and Harvey Macadam came into the starting XI in place of Anthony Pilkington and Ged Garner.
Oxford boss Karl Robinson named an unchanged side from their last outing, a narrow defeat at home to Sunderland. In Matty Taylor (22 goals) and Cameron Brannagan (13) they had two players who had found the net 35 times between them.
But Oxford, who arrived around 90 minutes before kick-off thanks to lengthy queues on the motorways, struck with less than two minutes on the clock as Nathan Holland netted his seventh of the season.
Billy Bodin’s cross from the right evaded the advancing Brannagan but Holland arrived right on time to place a neat finish into the bottom corner of the goal.
Not that it took Brannagan much longer to get on the scoresheet himself as, in the seventh minute, he exchanged passes with Holland and picked out the same corner his teammate had found earlier.
Brannagan picked out Bodin for the third, a firm header that was purely down to his determination to reach the cross while the nearest defender dawdled.
Callum Camps gave U’s keeper Jack Stevens his first nervy moment, crashing a free-kick from the edge of the box against the bar, and Ellis Harrison dragged a shot wide as Town finally showed signs of flickering into life.
And they got a helping hand five minutes before the break. Harrison tried to shoot through a packed penalty box and referee Bobby Madley spotted a hand being used, Sam Long the defender. Harrison fired in to cut the visitors’ advantage.
Brannagan’s shot was blocked but the ball fell for Taylor, who appeared to be offside, and he should have buried his finish but O’Hara got just enough on it.
The second half started with close calls at both ends, Stevens producing a fine save from Harrison’s header and Taylor seeing his tap-in chalked off for offside.
But Fleetwood were unrecognisable from the side that had daydreamed through the first 25 minutes and the game changed dramatically with Hayes’ goal.
The keeper was only able to push the ball into Hayes’ path and he sent it back past the prone keeper and into the empty goal, sparking belief in his own side and furious protests from the opposition.
But while Fleetwood did go closest with Paddy Lane’s shot, blocked by a desperate lunge, even with nine minutes added on they couldn’t find a third goal to complete what would have been a remarkable comeback.
Fleetwood: O'Hara, Nsiala, Clarke, Jules, Johnson, Macadam (Pilkington 70), Batty, Camps, Lane (Harrop 80), Harrison (Garner 90), Hayes; Subs not used: Butterworth, Baggley, Donaghy, Doyle.
Oxford: Stevens, Long, McNally, Moore, Brown, Bodin (Hanry 69, McGuane 88), Kane, Brannagan, Sykes (Williams 84), Taylor, Holland (Whyte 59); Subs not used: Eastwood, Forde, Seddon
Referee: Robert Madley; Attendance: 2,589