Two first-half goals did the trick for the Shrimpers, who might have added more.
They took the lead in the 13th minute as Asa Hall's poor clearance was pounced on by Conor Clifford, who hammered home a right-foot shot from 18 yards.
Dave Kitson went close for Oxford with a 30-yard drive that whistled past a post and Johnny Mullins had a header saved.
But Southend made it 2-0 on 30 minutes when centre back Luke Prosser was unmarked as he rose to meet Kevan Hurst's free-kick from deep and he headed down and past Ryan Clarke with ease.
Despite their lofty position, Oxford have managed just one home win this season.
James Constable, Michael Raynes and Mullins all went close with headers in the second half for the U's, while Cauley Woodrow missed a gilt-edged chance to make it 3-0 for Phil Brown's team.