Oxford won for the first time in five league games in a match that saw Histon miss two penalties.
Barry Quinn was penalised for handball but Antonio Murray struck the spot kick straight at Billy Turley.
Matthew Green volleyed Oxford ahead from six yards before Turley this time saved Adrian Cambridge's penalty after Luke Foster had fouled Murray.
Michael Howard extended Oxford's lead with a left-foot strike before Green secured the points with a header.
Oxford Utd: Turley, Day, Howard (Clarke 90), Quinn, Foster, Odubade (Anaclet 75), Murray, Hutchinson, Blackwood, Richards, Green (Fisher 84).
Subs Not Used: Trainer, Rose.
Goals: Green 33, Howard 45, Green 83.
Histon: Naisbitt, Pope (Midson 56), Gwillim, Mitchell-King, Ada, Okay, John Kennedy, Cambridge (Nightingale 78), Barker (Knight-Percival 63), Wright, Murray.
Subs Not Used: Key, Langston.
Ref: S Beck (Essex).