Histon recorded a seventh successive league win to move to the top of the Blue Square Premier.
Nathaniel Knight-Percival scored from just inside the area before Jack Midson doubled the lead from close range and Chris Willmott headed in for Oxford.
Knight-Percival fired into the roof of the net to make it 3-1 and Danny Wright extended the lead from 12 yards.
Mat Mitchell-King slotted a fifth for Histon before Eddie Hutchinson headed in a consolation for the visitors.
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