Grays keeper Rob Beckwith was carried off with a serious facial injury as Oxford led from the start to win.
Beckwith had 20 minutes of attention on the field after taking an accidental kick to the face from Lewis Haldane.
Oxford led through Kevin Sandwith's neat finish and two close-range efforts from James Constable, the second after Grays' Stuart Elliott was sent off.
Tony Dinning's free kick pulled one back for Grays before Adam Chapman completed Oxford's scoring.
Oxford Utd: Turley, Batt, Willmott, Foster, Sandwith, Odubade, Chapman, Clist, Haldane (Carruthers 67), Murray (Farrell 58), Constable.
Subs Not Used: Hinchliffe, Day, Hutchinson.
Booked: Clist.
Goals: Sandwith 8, Constable 26, 45, Chapman 69.
Grays Athletic: Beckwith (Arnold 45), Gier, Stuart, Dinning, Beavan (Quistin 70), Cogan, Elliott, Thurgood, Slabber, Pugh, Hudson-Odoi (Davis 45).
Subs Not Used: Wilnis, Lindie.
Sent Off: Elliott (41).
Booked: Elliott, Thurgood, Quistin.
Goals: Dinning 62.
Att: 4,764
Ref: Mark McLaughlin (Hampshire).
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