A lively start saw Oxford winger Sean Rigg go close against his former club before Vale's Tom Pope clipped the crossbar in reply.
But defences remained largely in command before Pope poached his 13th goal of the season in the 30th minute. Visiting goalkeeper Ryan Clarke failed to hold Louis Dodds' low shot from Ashley Vincent's left-wing cross and Pope fired in the loose ball from six yards.
Vale then took command and another Vincent delivery almost led to an own goal as the ball skimmed off John Mullins' head and struck the far post.
Vincent wasn't to be denied, however, as he netted Vale's second goal from the tightest of angles six minutes after the interval. Clarke hesitated after Sam Morsy played a ball over the top and Vincent chased down what appeared a lost cause to slice a left-foot effort into the far corner of the net.
It was all over 10 minutes later when Morsy bent in a terrific right-foot shot from 25 yards after Jennison Myrie-Williams laid on the chance. Myrie-Williams mesmerised Oxford at times and he almost bagged the goal his performance deserved when he rattled the crossbar late on.