Tom Craddock ended a year of injury frustration with the goals that sent Oxford to a second successive League Two win.
The former Middlesbrough and Luton forward missed most of the 2011-2012 season with knee and hamstring injuries but came on as a half-time substitute against ten-man Southend and broke the deadlock nine minutes later, turning in Alfie Potter's cross.
Southend spent more than an hour with ten men after midfielder Michael Timlin was sent off on 27 minutes for a second bookable offence.
Southend, who had lost 1-0 at home to Accrington last Saturday, got everyone behind the ball after that in the hope of holding out.
And Oxford took a while to start carving out good scoring opportunities.
Deane Smalley, preferred to James Constable at the start, screwed a shot wide from a good position, and just before the break Sean Rigg saw a superb flicked header pushed away by Cameron Belford.
Belford also saved brilliantly from Rigg's low drive just after Craddock had opened the scoring.
Craddock struck again on 87 minutes, driving an unstoppable shot past the over-worked Belford to secure the 2-0 success.