Quincy Owusu-Abeyie came off the bench and opened the scoring for the visitors at St Mary's.
Rickie Lambert levelled shortly after but Aruna Dindane, Nadir Belhadj and Jamie O'Hara netted to give the scoreline a flattering look for the bottom club in the Barclays Premier League.
This clash gave a reminder of the bitterness which exists between the two south-coast clubs, who had not met each other since Southampton's relegation from the Premier League in 2005.
Portsmouth look to be heading that way too and are adrift at the bottom of the table - but simply staying in business this week was the aim. They head back to the High Court next month as Her Majesty's Revenue and Customs push for a winding-up order.
Southampton know all about the effect financial troubles can have after dropping down to League One and suffering a points deduction this season for going into administration.
Pardew's men, however, are in decent form and will take huge encouragement from matching their top-flight neighbours - at least until the goals began to flow.
Morgan Schneiderlin had a long-range effort early on, then the hosts got even closer when Lambert swung a cross from the left to the far post.
It was inch-perfect for Papa Waigo N'Diaye and the striker headed firmly towards the bottom corner - but David James was down sharply and gathered at the second attempt.
O'Hara was responsible for Pompey's first efforts on goal, first with a 35-yard free-kick that went just wide of Kelvin Davis' post, then with a drive that the Southampton goalkeeper tipped over the crossbar.
Southampton continued to attack and N'Diaye was close to getting on the end of a couple of slick moves.
They were presented with another decent chance when James fumbled Lambert's corner. The ball raced onto the head of Radhi Jaidi and his effort went over the crossbar.
James then blocked at point-blank range just before the break when Wayne Thomas got on the end of another Lambert corner.
After going into the interval the happier of the two sides, Southampton did not let half-time break their stride.
James was required to pull off another fine save just after the restart. This time Michail Antonio cross to the back post and Adam Lallana met it with his head. James looked to be heading in the wrong direction but adjusted his feet to claw away.
Dindane gave the hosts a warning when he went just wide from the edge of the area, then John Utaka cut in from the left and forced a save from Davis.
Pompey boss Avram Grant made his move just before the hour mark, introducing Quincy for Angelos Basinas and giving his side a more attacking look heading into the final third of the match.
Quincy got into the action straight away with a run down the left and was welcomed with a crunching tackle from Dean Hammond, earning the Saints skipper a booking.
It was pure adrenaline from Hammond as his side were scenting an upset. If Lallana got more power on a volley when sent through, James would have been severely tested again.
Quincy struck in the 66th minute after Hassan Yebda crossed from the right and Utaka worked the ball to the substitute.
The former Arsenal forward took a touch to steady himself and then coolly curled home from just inside the penalty area.
The lead lasted just four minutes as Lambert headed in at the far post from a free-kick - but Pompey were ahead again shortly after the leveller.
Hayden Mullins started the move down the right before Quincy sent Dindane through to chip Davis for his second goal this week after netting against Sunderland.
Saints substitute Lee Barnard had a strike chalked off for offside late on, then Belhadj added a third when he raced through and sold Davis a dummy before finishing. O'Hara volleyed home the fourth after a sweeping move.