Former Blue Gary Roberts netted a penalty in the 32nd minute and Marc McNulty added a second five minutes later to give Portsmouth a comfortable 2-0 lead over Town in their third round replay at Fratton Park at half-time.
Boss Mick McCarthy named the anticipated entirely changed XI from the side which drew 1-1 with Preston on Saturday.
Bartosz Bialkowski returned in goal with Josh Emmanuel at right-back, Myles Kenlock left-back and Piotr Malarczyk and Paul Digby the centre-halves, as they were in the first game between the sides at Portman Road 10 days ago, which ended 2-2.
In midfield, Luke Hyam skippered and was joined in the centre by Jay Tabb with Ainsley Maitland-Niles on the right and Tommy Oar on the left. Up front, former Pompey striker Luke Varney was partnered by Brett Pitman.
The bench featured Joe Robinson, Kyle Hammond and Shane McLoughlin, all yet to make a first-team appearance, and Adam McDonnell, whose only previous senior game for the Blues came in the Capital One Cup at Doncaster.
Portsmouth named both their ex-Town players, keeper Brian Murphy and winger Roberts, in a team featuring three changes from their team at Portman Road with skipper Michael Doyle, Gareth Evans and Christian Burgess replacing Danny Hollands, Ben Close and Adam McGurk.
The home side created the game’s first opening in the third minute when Kyle Bennett was sent in on the left of the area but hit his shot across the advancing Bialkowski and wide.
Town threatened for the first time a minute later when Pitman reacted quickly to reach an under-powered Doyle header back towards keeper Murphy, but looped the ball on to the roof of the net.
But as in the first game the League Two side were seeing most of the ball and on nine Roberts shot straight at Bialkowski.
Malarczyk was handed the game’s first yellow card for blocking Marc McNulty in the 14th minute. Roberts slammed the freekick against the wall.
The Blues started to come more into it after the quarter-hour, Pitman’s header from Maitland-Niles’s cross from the right was diverted away, then the former Bournemouth man tried to slip Varney in on goal, but the ball caught the one-time Pompey striker’s heels.
But the home side were still having more of the ball and on 19 Bennett cut in from the left and scraped a shot wide.
Emmanuel did well to get in front of Evans on 21 as he looked to head home Ben Davies’s dangerous cross from the right.
Neither side was able to create another opportunity until the 31st minute when Barton played in McNulty but Bialkowski quickly came off his line to block.
However, the home side kept hold of the ball and got it back in the box where Roberts was scruffily felled by Malarczyk. Referee Andy Woolmer considered his decision before pointing to the spot, leading to Blues’ protests, although the Pole kept out of it having already been booked.
The ex-Town winger took the kick himself and Bialkowski was unfortunate not to save it, diving to his left and clawing it into the opposite corner of the net with his right hand.
Bennett hit a weak effort through to Bialkowski, before the home side increased their lead in the 37th minute. Evans drifted a cross over from the right and McNulty placed a header past the Blues keeper from six yards.
Having gained their two-goal lead Portsmouth had their tails very much up and were continuing to take the game to the lacklustre Blues. Just before half-time, McNulty was threaded in on goal but Bialkowski came off his line quickly to claim.
The home side were good for their two-goal lead at the break having created the game’s best opportunities - Pitman’s early moment of opportunism the nearest the Blues came to a goal - and as at Portman Road having played the better football.
Aside from a spell in the middle of the half prior to the goals when they had been unable to create a chance, much-changed Town had been on the back foot throughout.
Portsmouth: Murphy, Davies, Webster, Burgess, Stevens, Barton, Doyle (c), Evans, Roberts, Bennett, McNulty. Subs: Bass, May, Close, Tollitt, Naismith, McGurk, Chaplin.
Town: Bialkowski, Emmanuel, Digby, Malarczyk, Kenlock, Hyam (c), Tabb, Maitland-Niles, Oar, Varney, Pitman. Subs: Gerken, Robinson, Hammond, Coke, McDonnell, Touré, McLoughlin. Referee: Andy Woolmer (Northamptonshire). Att: 15,179 (Town: 796).