The U's remain three points off the top seven after their heavy reverse, and will be aiming to bounce back straightaway on Tuesday night against Mansfield.
Pompey took a 1-0 lead into the interval and it was a second goal moments after the restart that gave them a stranglehold on the game that they were never going to let go of.
Colchester United lost 4-0 to an impressive Portsmouth side, as the visitors strengthened their top three credentials.
Portsmouth started the better of the two sides and found themselves a goal up through on-loan striker Eoin Doyle as he stooped low to head home from close range after a good cross from Kai Naismith.
Before the first goal, Portsmouth had several opportunities as Carl Baker flashed a dangerous cross right across goal and Naismith had a shot that was comfortable for Sam Walker.
Colchester hadn't really got going and had to wait until the 33rd minute for their first chance as Sean Murray had an acrobatic volley from the edge of the area, but other than this it was the away side that held the territorial advantage.
In the 37th minute, a neat one-two on the edge of the area allowed Enda Stevens to progress inside the area but his cross had too much power on it and went just wide.
Two minutes later Eoin Doyle latched onto a long ball over the top after George Elokobi made an error in judgement but the striker was unable to get his second of the game as he put the ball over the bar.
The second half saw Portsmouth dominate throughout and they doubled their lead just two minutes into the second half. Kyle Bennett smashed the ball into the net from close range after Naismith unselfishly squared the ball to the winger from 10 yards out.
Bennett should have added a third shortly after as Colchester switched off from a throw in but the winger put his shot wide after cutting in from the angle.
Portsmouth didn’t have to wait long to wrap the game up, though, as Danny Rose was slipped through on goal by Doyle and had the simple task of tapping in from close range after his initial first shot was saved by Sam Walker.
The visitors were well in control by this point and added a fourth from a lightning quick counter attack as Michael Doyle scored a tap in. The experienced midfielder followed in a rebound as Naismith's initial shot was well saved by Walker.
Portsmouth were able to see the rest of the game out comfortable as Colchester were unable to break through a strong Pompey defence and the game finished 4-0 to the visitors.
Colchester will now have to regroup and look to get back to winning ways as they host Mansfield Town on Tuesday, with both sides having an eye on the teams above them.