Kal Naismith grabbed an early opener, although the visitors responded well and it looked as though there might be a nervy finale.
That all changed when Alex Mowatt saw his penalty saved and was promptly sent off for lashing out at Nathan Thompson.
There was only going to be one winner from that point and Brett Pitman twice capitalised on good work from Jamal Lowe to wrap things up.
There was a single change from the side that won away at snowy Oldham the previous week.
Thompson came straight back into the starting line-up after returning from a four-match ban, with Brandon Haunstrup dropping to the bench.
A fit-again Gareth Evans – who had missed the same number of games with a hamstring injury – had to be content with a place among the substitutes.
There were a couple of familiar faces in the visitors’ line-up, with former Pompey players Simon Eastwood and Wes Thomas both featuring.
The hosts made a bright start and the fans inside Fratton Park – as well as those watching on Sky Sports – had a goal to celebrate in just the fifth minute.
Connor Ronan sent a corner into the box and Matt Clarke nodded it back into the centre, where NAISMITH was waiting to hook home from close range.
He might have had a second after getting down well to meet another Ronan delivery with a diving header that flashed wide.
Oxford were all over the place and Ryan Ledson collected an early booking following a late challenge on the energetic Ronan.
Eastwood then grabbed Dion Donohue’s free-kick before Naismith could make a connection, while a cross from the Scottish forward had to be turned past his own post by Ashley Smith-Brown.
But United improved as the half progressed and James Henry turned sharply on the edge of the box before crashing a shot against the bar.
The Blues soon had a chance at the other end, with Lowe’s centre agonisingly out of reach for Pitman, as the skipper slid in at the far post.
Pitman was then brought down by Rob Dickie as he burst through on goal. The Fratton faithful were baying for a red card, but referee Charles Breakspear instead brandished a yellow.
It was Oxford who dominated as the interval approached, though, and Malachi Napa’s effort was diverted wide by Luke McGee’s fingertips.
Then, from the resulting corner, a well-placed Pitman had to hack Dickie’s goal-bound header from the line.
And the United defender should have done better just before the break, rising at the far post to meet a corner, only to send the ball wide from just a few yards out.
Oxford United 0
Oxford were still on top in the early stages of the second half, with Jack Whatmough doing well to deal with Todd Kane’s dangerous cross.
And the hosts made a change after just 51 minutes, with Evans making a welcome return to action in place of Ronan.
Pompey were struggling to keep hold of the ball and United were growing in confidence as they pushed forward, without forcing McGee into too much action.
And it looked as though the visitors would draw level just past the hour mark – only to miss a penalty and then be reduced to 10 men.
Clarke was penalised for a tug on Dickie inside the box, with Mowatt sending the spot-kick cannoning against the post.
The Oxford forward immediately clashed with Thompson, lashing out to send the Blues player tumbling to the turf.
That sparked a melee, involving plenty of pushing and shoving. When it all calmed down, Breakspear booked McGee for his reaction, before dismissing Mowatt.
It did not take long for the hosts to make the most of their numerical advantage, with the lead doubled on 69 minutes.
The delivery from Lowe on the right was superb and PITMAN was there to lash the ball into the roof of the net from a few yards out.
Pompey were, unsurprisingly, completely on top, with Evans seeing a shot blocked as home players started to fancy seeing their name on the scoresheet.
Instead it was the familiar figure of PITMAN who extended the advantage – with Lowe again playing a key role.
He raced onto a Thompson pass and rounded Eastwood with ease, only to be forced wide.
But the winger maintained his composure and squared for the Blues’ top scorer to stab into the net and complete an enoyable afternoon.
Pompey (4-1-4-1): McGee; Walkes, Whatmough, Clarke, Donohue; Thompson (May 87); Lowe, Close, Ronan (Evans 51), Naismith; Pitman (c)
Goals: Naismith 5, Pitman 69, 79
Booked: Thompson, Naismith, McGee
Subs not used: Bass, Burgess, Haunstrup, Kennedy, Chaplin
Oxford (4-1-2-1-2): Eastwood; Kane, Dickie, Mousinho (c), Smith-Brown (Ricardinho 77); Brannagan; Ledson, Mowatt; Henry (Mehmeti 77); Napa (Rothwell 66), Thomas
Sent off: Mowatt
Booked: Ledson, Dickie, Brannagan
Subs not used: Shearer, Martin, Ashby, Ruffels
Referee: Charles Breakspear
Attendance: 17,892 (1,050 away fans)