Australian striker John Aloisi scored his 10th goal of the season as Portsmouth picked up a valuable Worthington Cup first leg lead.
Wimbledon manager Joe Kinnear left out nine of the players who had performed at Aston Villa only three days ago.
Chris Perry and Ben Thatcher were the only survivors from that side and Perry was taken off at half-time as Kinnear looked for ways of limiting the damage.
Pompey took full advantage of the re-shuffle in the Wimbledon ranks to go two goals ahead in 25 minutes.
Aloisi raced clear onto a defence-splitting pass from Fitzroy Simpson to beat Paul Heald with a fierce right-foot shot.
There was still disorganisation among Wimbledon defenders when Portsmouth scored again as Simpson streaked down the left to get in the centre which appeared to strike Alan McLoughlin last before going over the line.
Only then did Wimbledon begin to show their Premiership class and they were thrown a lifeline when Carl Court dispossessed defender Adrian Whitbread to set up an easy chance for Efan Ekoku to score his fourth of the season.
Kinnear ripped into his players during the interval and made three substitutions and Wimbledon were a much-improved side after the break.
But for all their incessant pressure they failed to trouble Pompey's veteran goalkeeper Alan Knight apart from when a header from Court went narrowly wide.
Portsmouth might even have scored a third when a poor back pass from Brian McAllister let in Aloisi but Heald made a brave block to leave Wimbledon with a chance of winning the home leg.