United had already gone ahead through Sean Rigg by the time Jamie McGuire saw Stags' sixth red card of the season after 23 minutes.
Mansfield had scored eight times in the FA Cup the week before, but when Lee Stevenson bagged a stoppage-time equaliser, it was their first league goal for 472 minutes.
However, substitute James Constable restored Oxford's lead four minutes later, two minutes after coming on, and Ryan Williams sealed it with a third after the break.
The win means Oxford have won six and drawn two of their eight games on the road this term while Stags are now without a win in seven league games.
Mansfield might have grabbed a ninth-minute lead when Ryan Clarke had to make a good reaction save to keep out Stevenson's flicked header from a corner.
But three minutes later it was Oxford who drew first blood as home goalkeeper Alan Marriott tamely parried what looked a routine stop from Rose's low shot into the path of the lurking Rigg for a simple close-range tap-in.
Stags were then rocked when McGuire was shown a straight red for diving into a tackle on Rigg.
With so many stoppages there were eight minutes added on at the end of the half during which two goals flew in.
First Stevenson levelled for the 10 men with a crisp volley down the centre after a John Dempster effort was half-cleared.
But Constable was then sent into the action and quickly restored the visitors' lead as he turned a neat Williams pass into the net off the inside of a post.
United always looked the more likely to score after the break and their crucial third goal arrived after 66 minutes as Williams turned home Rigg's low cross from close range.