The opening exchanges of the game were fairly even as both teams only dealt in half chances.
However, Oxford saw themselves two up at the break after hitting Margate with two goals late in the half.
Firstly, Geoffrey Poku picked up a stray pass, burst down the right before slotting past John Henley at his near post.
Then in injury time Robbie Cundy turned home Tom Winter’s cross from close range to extend his side’s lead.
Needing a big second half performance to rescue the game, Margate were done on the break just two minutes after half-time when Winters waltzes into the box and calmly shot past Henley.
Michael Fondop lifted a forth over Henley after being put in behind Margate’s defence, minutes after stepping off the bench.
Margate’s day got even worse moments later after Lewis Taylor was giving his marching orders for a second booking following a late challenge.
Winters nodded over the bar from close range and John Henley saved well from James Roberts, after having to rush from his area, as Oxford pushed for a fifth goal.
They grabbed that goal on 87 minutes, as Fondop passes the ball into an open net after receiving a pass from the by-line.
Margate: Henley, Sessegnon, B Johnson, M Johnson (Foster 81), Parry, Fitzsimons, Taylor, Moore, Barrington (Phipps 70), Rowland (Osei 45), Osborn. Subs not used: Tumwa, Kallmeier.
Oxford City: Belford, Poku, Grant (Ngathe 70), Ashby (Davies 70), Henderson, Cundy, Giles, Fleet, Roberts, Louis (Fondop 60), Winters. Subs not used: Ofuso.