Luton Town defender Luke Wilkinson scored a second-minute header, and his first since March 2013, to give his side the lead going into half time.
Hatters striker Shaun Whalley was brought down shortly after kickoff, resulting in a Jake Howells free kick headed in by Wilkinson early on.
Pelly Ruddock Mpanzu almost doubled the hosts' lead a minute after, with the midfielder powering his shot just wide.
Oxford had long spells of possession but it rarely resulted in any strong chances.
Kenilworth Road started to see end-to-end action as the Hatters looked to double their lead and Oxford were hoping for an equaliser.
However, it was Wilkinson's header after 80 seconds that separates the two sides at half time.