Lightning struck twice but not a third time for Wanderers as their four-game unbeaten run came to an end.
After two successful fightbacks had brought maximum points in their last two League One games, the Whites couldn’t do it again as Oxford nipped a comeback in the bud to enhance their impressive recent run.
When Dion Charles struck his sixth goal of the season to make it 2-1 with more than 20 minutes go – including that added on at the end – Ian Evatt’s men looked as though they might again finish with a flourish.
But Oxford’s third goal, headed in from a corner by substitute Steve Seddon, just six minutes later killed the hope as the savvy U’s extended their unbeaten run to four games and slowed Wanderers’ climb up the table.
The Whites remain sixth in the table ahead of a break for FA Cup action but were well short of their best as they failed to build on the momentum of the past week.
Wanderers made four changes to their starting line-up following their late, late show in mid-week but were without the ill Amadou Bakayoko, whose equaliser via the bench had launched the fightback against Burton.
Josh Sheehan’s role in that comeback earned the midfield man a first league start in 11 months, alongside the returning Kieran Lee and MJ Williams.
But after a bright start it became a familiar tale as the Whites fell behind for the third game running.
Oxford had shown more ambition than Burton on Tuesday night but hadn’t really threatened when they grabbed the lead.
Kyle Joseph caused the problems with a run down the left and from his low cross, Djavan Anderson bundled the ball home after an initial effort from Gatlin O’Donkor had been blocked.
Long throws also offered the visitors some encouragement and after the ball had again bounced around the Wanderers' box only a fine block from James Trafford from Elliott Moore's close-range header prevented Oxford from doubling their lead.
But Evatt's men should have been level by the break.
Not all of their attempts to unpick the U's defence had been successful but after working the ball nicely across the penalty area, Connor Bradley fed the over-lapping Gethin Jones for a cross Sheehan thought he had converted until his effort hit the legs of keeper Simon Eastwood and somehow bounced clear.
Once again, Wanderers had to try and do it the hard way and seven minutes into the second half the task got harder still as Oxford went 2-0 up from their first foray forward of the half as Ciaron Browne picked up the ball, strode forward and smashed a swerving strike into the bottom corner from close to 25 yards out.
The Whites needed a response and after a further double change from the bench it could have come from Jon Dadi Bodvarsson.
The striker had made an instant impact with his mid-week winner but after being picked out by Jones following another excellent burst forward from the Welshman, he mis-cued his attempted finish before firing over the top after retrieving the loose ball.
With 20 minutes to go the margin for error was decreasing but with Charles pouncing to halve the deficit, suddenly the hope was back.
Kieran Sadlier had helped liven up the Whites following his introduction and his link-up with Bradley ended with a fine pass from Bradley in behind the Oxford defence which Charles met on the run to tuck the ball calmly under Eastwood and end his six-game wait for a goal.
The crowd responded as they sensed another rescue mission and Charles was then only inches away from an equaliser as he stretched to try and reach Aaron Morley's cross.
But the Whites’ impetus didn't last long as Oxford restored their two-goal advantage with 78 minutes gone.
Trafford initially saved well from Marcus Browne but from the second of two corners Seddon managed to get his head on the ball in a crowded six-yard box and nod home.
It was a disappointing goal to conceded and this time there would be no spark to re-light Wanderers’ fire as they succumbed to just a second home defeat at the end of a busy month and an eight-game run which finally took its toll.
Wanderers: Trafford; Jones, Almeida Santos, Johnston; Bradley, Lee (Sadlier 66), Williams (Morley 66), Iredale (Afolayan HT); Sheehan (Dempsey 60); Kachunga (Bodvarsson 60), Charles. Substitutes: Thomason, Beck.
Booked: Williams, Almeida Santos
Oxford United: Eastwood; Long, Moore, Findlay, Brown; McGuane; Anderson (Henry 80), Bate (Goodrham 80), Brannagan (Rodfriguez 80), Joseph; O'Donkor (Browne 70). Substitutes: McGinty, Jones, Henry.
Booked: O'Donkor, Brannagan, McGuane, Rodriguez
Referee: Ollie Yates
Attendance:17,281 (558 Oxford)