John Marquis opened the scoring from the penalty spot, while Ronan Curtis added a goal in each half to secure all three points.
It means that next month’s Fratton contest against West Ham’s youngsters will merely decide who claims top spot in Southern Group A.
Kenny Jackett made 10 changes from the side that had beaten Burton in League One at the weekend.
Ryan Williams was the only player to keep his place in the starting line-up, with Rasmus Nicolaisen handed his debut at the heart of a three-man defence.
Alex Bass returned between the sticks, while Ben Close was handed the captain’s armband in Tom Naylor’s absence.
The other men handed a chance to impress were Haji Mnoga, James Bolton, Paul Downing, Cam Pring, Andy Cannon, Curtis and Marquis.
Despite all the alterations, the visitors looked bright from the beginning and created several early opportunities.
Williams dragged a shot narrowly wide from an acute angle, while Nicolaisen could not keep the ball down when he met Pring’s corner.
The former had another chance following a quick Blues break up the pitch, but was this time denied by Shrimpers stopper Mark Oxley.
And Pompey did break the deadlock midway through the first half following a clear foul on Mnoga by Tom Clifford.
Referee Paul Howard pointed straight to the spot and MARQUIS stepped up to calmly send Oxley the wrong way from 12 yards.
Southend had barely threatened, although Timothee Dieng should have done better than send his close-range header straight at Bass.
Matt Rush was then booked for a late challenge on Bass when the two raced to reach a loose ball first.
Oxley came to the rescue once more on 37 minutes, denying Marquis with his legs after Williams had stolen possession and slipped a pass across to the striker.
But he could do nothing to prevent the hosts falling further behind moments later, with a 25-yard CURTIS strike taking a wicked deflection off Richard Taylor to deceive the keeper.
There were more chances before the break, although Mnoga blazed one over the bar, while a rocket from Curtis flew just too high in stoppage-time.
Southend United 0
Pompey began where they had left off following the restart and Curtis hit a dangerous ball across the face of goal.
The visitors were then forced into a change when Lewis Gard went down injured and had to be stretchered from the pitch.
With the Blues coasting, however, the action was undoubtedly less intense and Bass was largely enjoying a watching brief.
There was a dangerous attack launched by Terrell Egbri, only for a perfectly-timed Mnoga challenge to stop him in his path.
Nicolaisen livened things up just past the hour by meeting Cannon’s corner with a firm header, but Oxley made a super stop to deny the Dane a debut goal.
Bass then appeared to tip over a header from Harry Kyprianou, although Howard infuriated the home side by failing to award a corner.
The visitors were still looking more likely to add to the scoring, however, and they duly wrapped things up on 77 minutes.
It was a fine solo effort from CURTIS, who was afforded space to surge forward before depositing a long-range strike into the bottom corner of Oxley’s net.
That was his last piece of meaningful action, as – perhaps with Saturday in mind – he was soon replaced by Callum Johnson.
And the closing stages passed by without much incident, as Pompey’s fine record in the EFL Trophy continued.
Southend (4-4-2): Oxley (c); Hobson, Dieng (K.Coker 46), Taylor, Clifford; Egbri, Gard (O.Coker 52), Phillips, Kyprianou; Acquah (Nathaniel-George 74), Rush
Booked: Rush, Taylor
Sub not used: Seaden
Pompey (3-4-3): Bass; Bolton, Dowing, Nicolaisen; Mnoga, Close (c), Cannon, Pring; Williams (Morris 88), Marquis, Curtis (Johnson 80)
Goals: Marquis 21 (pen), Curtis 40, 77
Subs not used: MacGillivray, Raggett, Jacobs, Harness, Harrison
Referee: Paul Howard