But a red card brandished to James Henry, who clawed the ball off the line and denied The Dons an equaliser, changed the game.
The resulting penalty was put away by Joe Pigott, who scored his 20th of the season in the process.
The turnaround was complete just two minutes later, as Alex Woodyard majestically curled a left-footed shot past James Stevens to secure Mark Robinson’s side their fourth win on the bounce.
Mark Robinson called for his team to be ‘relentless’ in their final five games of the season, as he made one change from the side that beat Swindon Town 4-1 on Saturday, with Luke O’Neil dropping out in place of Cheye Alexander.
Oxford, desperate for all three points in their fight for a playoff place, started the game with an intense pace at Plough Lane.
Midfielder, James Henry, broke in-behind the Dons’ defence and tested Nik Tzanev, but the New Zealand goalkeeper was equal to the early effort.
The next clear-cut chance fell to Will Nightingale.
The centre back, who is enjoying an unexpected swansong in front of goal of late, was left unmarked inside the area. However, his tame header from a George Dobson cross, was easily collected by Jack Stevens.
After a tetchy 20 minute spell, the Oxford bench were incensed with rage when Sam Long went down inside the area under pressure from Cheye Alexander. However, referee Andy Davies waved play on.
George Dobson was next to try his luck, taking aim from 25-yards out, but Jack Stevens pushed the ball away to safety.
The attritional first half was met by a scintillating second 45, with both sides hungry for three points for different reasons.
Cheye Alexander, who was gallivanting up and down the right-hand side, had the first effort on the 49th minute when he smashed a left-footed shot straight at Stevens in the Oxford net.
It would either take something breathtaking, or something incredibly fortuitous, to get past either of the two stubborn defences on show at Plough Lane - and it was the latter that allowed Oxford to take the lead.
Josh Ruffels picked up the ball just outside the box and drove a sweet strike into a melee of bodies in the box. The ball cannoned off the bewildered Nightingale deceiving Tzanev to roll into the back of the net.
Cameron Brannagan spotted Tzanev off his line and attempted an audacious lob from 35-yards which was dipping beneath the bar. But Tzanev atoned for his earlier mistake to spare any further blushes.
With Oxford brimming with verve – similar to the plans for the new European Super League – their evening was turned upside down in a matter of minutes.
A Will Nightingale header, which was destined for the back of the net, was clawed off the line, not by Jack Stevens, but by James Henry; prompting Andy Davies to reach for the red card and hand Joe Pigott the chance to score his 20th of the season from the spot.
Pigott personified coolness, sending Stevens the wrong way and breathing life back into Mark Robinson’s side.
With Oxford down to 10 men, and The Dons in full swing, it was no surprise to see the home side add a second within a matter of minutes.
After good work down the left from Nesta Guinness-Walker, Alex Woodyard arrived on the edge of the box to curl a left-footed strike into the roof of the net; sending the Dons bench into pandemonium.
The three points allowed The Dons to keep a five point gap between themselves and the bottom four; but they are the inform team heading into the business end of the season.
As for Karl Robinson’s side, the playoff dream is still very much alive.
However, with two games in hand around their league rivals, Oxford will have to hope results go their way if they are to sneak into the final spot.