Chris Wilder's side needed one point against his old club to keep the Cobblers up and goals either side of the interval from Ivan Toney and substitute Mathias Kouo-Doumbe sealed all three points after John Marquis had cancelled out Ryan Williams' opener.
Oxford started brightly and James Constable had a close range shot blocked before the visitors took a sixth minute lead. Danny Rose's inswinging corner was flicked on by David Kitson at the near post for Williams to turn and fire home from close range.
Toney should have equalised shortly afterwards when he raced through and rounded goalkeeper Ryan Clarke but his shot came back off the upright.
The lively Williams went close to a second goal when he fired over from the edge of the box. But Williams then got a straight red card for an off the ball incident with Cobblers skipper Ricky Ravenhill.
Chris Hackett twice went close to an equaliser against his old club before the equaliser arrived in the 29th minute when Toney flicked the ball on for Marquis to race into the box and beat Clarke with a low drive. And four minutes later Toney headed home a cross from Evan Horwood.
Cobblers twice went close on the stroke of halftime. Marquis was inches away when his near post flick just went just the wrong side of the far upright and Zander Diamond had a close range shot cleared off the line by Jake Wright.
But substitute Kouo-Doumbe increased Northampton's lead five minutes after the restart when he headed home Hackett's deep free-kick. Toney missed a great chance when he beat Clarke but Wright raced back to clear the ball off the line and substitute Emile Sinclair headed over.