The home side were unable to make the most of their overall control of proceedings and trailed at the break to Joe Ironside’s header.
Liam O’Neil doubled United’s advantage after the break and a fine strike from Ronan Curtis was not enough for the Blues.
Danny Cowley made five changes from the side that were narrowly beaten at MK Dons the previous week.
Miguel Azeez was handed his debut, while Mahlon Romeo made his Fratton bow and there were also starts for Ellis Harrison, Ronan Curtis and Paul Downing.
The latter replaced injured skipper Clark Robertson – with Lee Brown taking the armband – while Reeco-Hackett Fairchild, John Marquis, Joe Morrell and Kieron Freeman dropped to the bench.
There was a familiar face in the opposition line-up, with Fratton academy graduate Adam May starting in midfield.
It was a familiar story once the action got underway, as Pompey dominated possession without really testing Dimitar Mitov between the sticks.
In fairness, the visitors defended resolutely and the keeper did come off his line to collect some dangerous deliveries.
One dangerous move saw the Blues break quickly forward from a Cambridge corner, but Harrison was tackled inside the box after good work from Azeez and Marcus Harness.
Conor Masterson also made a key headed clearance when Brown tried to pick out Harrison at the back post.
It was one-way traffic, with Pompey showcasing some neat passing play as they sought a breakthrough.
But Cambridge went ahead against the run of play on 38 minutes, as Ironside hung in the air to meet George Williams’ cross, sending a header looping over Gavin Bazunu and into the net.
And they might have had a second before the break, with Bazunu getting down to deal with a long-range drive from May.
Cambridge United 1
The visitors appeared more than happy to sit back deep inside their own half when the action restarted.
It meant that Pompey had the freedom of most of the pitch, but getting inside the final third continued to prove problematic.
One break did provide an opening, as Harness found Harrison who slid the ball across goal for the advancing Ryan Tunnicliffe, only for Mitov to get there first.
Cowley made a double switch just before the hour mark, with Harrison and Azeez withdrawn for Marquis and Louis Thompson.
But United were next to threaten when a May corner was met by Ironside and his header deflected behind off Romeo.
Pompey’s third and final switch saw George Hirst replace Downing, meaning Shaun Williams dropped back into defence.
Their hopes of taking something from the game were dealt a huge blow on 69 minutes, however, as Cambridge doubled their lead.
May’s corner was only cleared as far as O’Neil on the edge of the box and he hit a half-volley into the top corner.
Hirst went down in the box under pressure from two defenders moments later, but his penalty cries were ignored by referee Gavin Ward.
And the striker then saw a shot blocked inside the box, only for the Blues to score just a few seconds later.
The ball ran loose for CURTIS, who hit a fine strike into the net from a tight angle to give the home faithful renewed hope.
Now the search was on for an equaliser, but Hirst’s shot lacked power after a neat turn on the edge of the area and Mitov made a comfortable stop.
Tempers flared in the closing stages and a bout of shoving in front of the Milton End led to Brown and George Williams both being booked.
The crowd were also growing frustrated by some apparent play-acting from the visitors to use up time, with seven minutes added on by the officials.
Pompey tried to snatch a point, but the closest they came was when Sean Raggett headed over from a Harness free-kick.
Pompey (4-1-4-1): Bazunu; Romeo, Downing (Hirst 67), Raggett, Brown (c); Williams; Harness, Tunnicliffe, Azeez (Thompson 59), Curtis; Harrison (Marquis 59)
Goals: Curtis 76
Booked: Williams, Brown, Curtis
Subs not used: Bass, Freeman, Morrell, Hackett-Fairchild
Cambridge (4-1-4-1): Mitov; Williams, Jones, Masterson, Iredale; Digby (c); Tracey (Dunk 87), May, O’Neil, Brophy; Ironside (Smith 74)
Goals: Ironside 38, O’Neil 69
Booked: Tracey, Digby, Williams
Subs not used: McKenzie-Lyle, Okedina, Weir, Lankester, Knibbs
Referee: Gavin Ward
Attendance: 15,330 (544 away fans)