Goalkeeper Billy Turley saved two penalties and Matt Green hit a brace as Darren Patterson's team recorded their first win in six matches with an impressive performance at the Kassam Stadium.
In truth, both Histon's penalties were weak efforts, but Turley still guessed right and got down well to save.
Green had a super game, and struck after 33 and 83 minutes, sandwiched either side of a fine drive from another new signing, Michael Howard.
There was much to be encouraged by United's performance as they inflicted Histon's heaviest defeat of the season.
Histon almost scored from one of Adrian Cambridge's long throws in the first minute, the set play causing panic in the Oxford defence before it was hacked clear.
The home side were low on confidence at the start and often laboured in their attacks, with their new players taking time to understand each other's runs, and when the visitors broke quickly, Antonio Murray was only halted by a crunching tackle from Luke Foster.
It was from the Stutes' first corner after a quarter of an hour that they won their first penalty, with Barry Quinn adjudged to have handled the flag kick as it came into the box.
But Murray's low right-footed spot kick was embarrassingly weak and Turley comfortably saved it to his right.
Oxford had been under the cosh for much of the first 20 minutes, but they then worked a couple of good openings.
Green saw a cross-shot deflect narrowly wide, and from the resulting corner swung over by Adam Murray, midfielder Eddie Hutchinson's flicked header flashed just past the far post.
Green then fired the U's in front with an excellent finish.
Matt Day picked him out in space in the area with a chipped pass, and the on-loan Cardiff striker hooked the ball home on the turn, keeper Danny Naisbitt just getting his hand to the shot but unable to prevent it flying into the net.
Steve Fallon's men then had a great chance to get back on level terms when they were handed a second penalty ten minutes before the break. This time Antonio Murray's trickery forced Foster into bringing him down, but once again Turley came to Oxford's rescue.
After Murray's terrible first penalty, Cambridge took the second one. But it wasn't any better, low and soft, and Turley made another comfortable stop down to his left.
If they had been buoyed by the first miss, United's players must have been ecstatic at the second, and convinced this was their day.
And right on half-time they doubled their lead. Justin Richards did well to hold off a defender, and let the ball run through to left back Michael Howard, who struck a ferocious left-footed drive through a crowded box and into the goal with the help of a deflection.
Histon rallied briefly in the second half and Turley had to reach up and save Danny Wright's header, inevitably from another Cambridge long throw.
Michael Blackwood, Oxford's newest signing, from Kidderminster, started to come alive as the game wore on, and he pulled back a cross for Green after a blistering run along the left, yet Green's finish was poor.
But there was no stopping the striker as he forced the ball home from close range when Hutchinson headed back Adam Murray's free-kick after Richards had been brought down just a yard outside the area.
Oxford Utd: Turley, Day, Quinn, Foster, Howard (Clarke 90), Odubade (Anaclet 75), Hutchinson, Murray, Blackwood, Green (Fisher 84), Richards. Subs not used: Trainer, Rose.
Att: 4,851
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