Luke Foster's late headed goal helped Oxford take all three points against struggling Lewes, for whom Elliot Charles missed a penalty.
Joe Keehan struck from 25 yards to open the scoring for Lewes, but Adam Murray's free-kick levelled the scores.
Charles saw his penalty kick saved by Billy Turley and they were made to pay as Foster headed in Craig Nelthorpe's corner to win it for Oxford.
Lewes' misery was compounded as Shaun Wilkinson saw red for violent conduct.
Oxford Utd: Turley, Batt, Willmott, Foster, Carruthers, Haldane, Chapman, Hutchinson (Odubade 55), Nelthorpe, Murray, Farrell (Day 90). Subs Not Used: Hinchliffe, Clarke, Taylor.
Booked: Murray.
Goals: Murray 17, Foster 82.
Lewes: Banks, Barness, Butters, Cullip, Fisk, Keehan, Breach (Foreman 83), Wilkinson, Cox, St Aimie, Charles. Subs Not Used: Winterton, Hall, Wallis-Taylor, Liburd.
Sent Off: Wilkinson (85).
Booked: Keehan, Cox.
Goals: Keehan 11.
Att: 4,595
Ref: Paul Melin (Surrey).
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