Stanley Mills scored a brilliant individual winning goal a minute from time to give managerless Oxford a 2-1 victory over Southampton at the Kassam Stadium.
Recalled midfielder Tyler Goodrham rifled the U's in front in the 23rd minute with a thumping drive from 20 yards as Saints struggled to clear a corner.
Southampton levelled six minutes later when centre-back Taylor Harwood-Bellis headed Leo Scienza's free-kick from the right past Jamie Cumming and into the bottom left corner of the net.
The match looked destined to finish as a draw but Mills had other ideas, running with the ball 50 yards, taking a return pass from Will Lankshear, then hitting a low angled shot under keeper Gavin Bazunu.
Craig Short was placed in temporary charge of Oxford following the sacking of Gary Rowett on Tuesday, with the team having won just one of their last 10 matches.
This was the first league meeting between these clubs since a goalless draw in the top flight back in April 1988.
Short made several changes from the defeat at Charlton before Christmas, bringing back Jack Currie, Luke Harris, Mills and Przemyslaw Placheta, as well as Goodrham.
Harris delivered the game's first shot, from distance, but it was a comfortable save for Bazunu.
Saints started to have a lot of the ball, and they had shouts for a penalty turned down when Scienza was sandwiched by two Oxford defenders on a run into the box.
The visitors forced the first corner, in the 20th minute, and when it was only half-cleared, Finn Azaz blazed over from a good position nine yards out.
Three minutes later, from Goodrham's own flag kick that was only half headed out to just outside the area, the midfielder smashed a high shot past Bazunu's right hand.
But Tonda Eckert's men did not take long to get back on level terms, thanks to the quality of Scienza's free-kick delivery and a clinical Harwood-Bellis finish.
Scienza was looking a class act, and the Brazilian took Azaz's pass and hit a left-footed shot against a post, despite the presence of two close markers.
Scienza then had a header saved, as the visitors finished the half on top.
Oxford began the second period with Placheta firing in a 20-yard volley that Bazunu turned around his post.
Substitute Jay Robinson went close for Saints with a dribble past two defenders and low shot that Cumming smartly saved by his near post.
But Mills was proving a big threat on the left wing for United as the contest became end to end.
Adam Armstrong nearly won it for Southampton 11 minutes from time, from Azaz's cross, but Cumming somehow saved with his leg.
And then Mills won it in dramatic style for the home side.
The managers
Oxford's Gary Rowett:
To follow...
Southampton's Tonda Eckert:
To follow...