James Constable earned Oxford their first win in six games and ended Plymouth's five-match unbeaten run.
Constable scored his 11th goal of the season when he diverted Damian Batt's angled drive past goalkeeper Jake Cole.
The striker could have had a hat-trick but opted to pass instead of shoot when through, before later hitting the post.
Argyle's Jason Banton was denied by ex-Plymouth keeper Luke McCormick, while Oxford captain Jake Wright cleared Reuben Reid's header off the line.
Constable's 91st goal for the club now puts him third in Oxford's all-time top goalscorers list, above Peter Foley and John Aldridge.
VIEW FROM THE DRESSING ROOM
Plymouth Argyle manager John Sheridan told BBC Radio Devon:
"It was very disappointing, you wouldn't think we were a team unbeaten in four.
"It was a great opportunity to push away from one or two teams at the bottom that were close but we just didn't get going at all.
"I have a big downer on people who are sloppy because they get paid good money and they should be able to go out and perform better than they did."