Oxford inflicted a fifth consecutive defeat on AFC Wimbledon to move within a point of the play-off places.
James Constable scored his ninth goal of the season with a left-footed finish to give the U's an 18th-minute lead.
Asa Hall's simple header on the stroke of half-time gave the visitors a two-goal interval advantage.
The Dons had chances in the second half, notably when Ricky Wellard played in Rashid Yussuff, who smashed the ball against the underside of the bar.
AFC Wimbledon manager Terry Brown told BBC London 94.9:
"I would like to say we were really unlucky today but we're not unlucky if you have a first half performance like that. The first half just wasn't good enough. We went in 2-0 down as we have done in the last couple of home games.
"It is difficult when you're working hard like we are in training and nothing is coming off for you on a Saturday.
"If we're not scoring goals we're not going to win games. There is no magic wand to wave. Just more hard work."