OXFORD United put in a lethargic and completely disjointed display as they fell to their first home defeat under Gary Rowett.
Portsmouth midfielder Andre Dozzell scored two minutes into the second half after a medical emergency had led to a delay of more than half an hour during the first half.
The visitors then wrapped up all three points when substitute Mark O’Mahony was played down the centre and finished smartly.
Rowett made just the one change to the side which was held to a goalless draw at Derby County on Tuesday night, as Ruben Rodrigues replaced Alex Matos.
Within the first 20 seconds, former U’s winger Josh Murphy was presented with an early sight of goal, but he struck low into the gloves of Jamie Cumming from the edge of the penalty area.
Colby Bishop then headed wide at the near post from a left wing Murphy cross shortly before a wonderful minute’s applause to celebrate the life of Joey Beauchamp. On Wednesday, it will be three years since the United legend’s death.
There was then a delay of more than half an hour due to the medical emergency in the home end of the north stand, with the game paused by the referee.
The players returned to the pitch after the supporter received treatment from the emergency services, with play resuming at 1:15pm.
The U’s had a sight of goal when Siriki Dembele played the ball across the penalty box to Przemyslaw Placheta, who teed up Cameron Brannagan from the edge of the area, with the shot deflected behind for a corner.
Placheta then cut inside and saw a left-footed effort take a nick and loop just over the crossbar.
In first half stoppage time, Greg Leigh was forced off with a muscular problem in his leg, and Sam Long replaced him in a direct switch at left back.
Two minutes into the second period, Pompey took the lead after United failed to clear their lines during a goalmouth scramble from a corner, allowing Dozzell to tuck home a loose ball from a couple of yards out.
As the game approached the hour mark, Long was dispossessed by Matt Ritchie, who fed Callum Lang through the middle, but the stinging strike was claimed by Cumming.
The U’s were desperately lacking cohesion or control, and when they did have the ball, the decision-making was sloppy and littered with mistakes.
Rowett made a triple change in an effort to rectify that with 66 minutes on the clock, introducing Tyler Goodrham, Stan Mills and Ole Romeny for Rodrigues, Dembele and Mark Harris.
Placheta moved out to the left-hand side, with Mills on the right. Goodrham then took up the central position behind Romeny up front.
Romeny soon displayed a creative spark, playing an excellent ball from deep on the right-hand side, with Placheta arriving at the back post, only for Pompey goalkeeper Nicolas Schmid to get off his line quickly and thwart the winger.
Just before seven minutes of second half injury time were signalled, Mills produced a wonderful cross from the right-hand side, with fellow substitute Matt Phillips crashing a header over the crossbar from inside the six-yard box.
United finally started to pile on the pressure in stoppage time, but were undone at the other end when Terry Devlin slid O’Mahony through, and the striker finished smartly past Cumming.
Oxford United (4-2-3-1): Cumming; Kioso (Phillips 84), Helik, Brown, Leigh (Long 45+5); Vaulks, Brannagan; Placheta, Rodrigues (Goodrham 66), Dembele (Mills 66); Harris (Romeny 66).
Unused subs: Ingram, ter Avest, Matos, El Mizouni.
Booked: None.
Portsmouth (4-2-3-1): Schmid; Swanson (Devlin 84), Matthews, Atkinson, Ogilvie; Hayden (Pack 84), Dozzell; Ritchie (Aouchiche 63), Lang (Bramall 67), Murphy; Bishop (O’Mahony 63).
Unused subs: Archer, Poole, Gordon, Saydee.
Booked: Dozzell, O’Mahony.
Referee: Will Finnie (Bedfordshire)
Attendance: 11,423 (TBC visitors)