Fernando Torres was restored to the Reds attack but it was Pompey who took the lead through Nadir Belhadj on 33 minutes.
The Algerian winger started the move by nutmegging Emiliano Insua to set up an attack. When the ball was cleared, Kevin-Prince Boateng forced Pepe Reina into a save with a powerful volley, former Pompey full-back Glen Johnson failed to clear the ball and Belhadj lashed in at the near post.
Mascherano was given a straight red card just before the break for a tackle on Tal Ben Haim that saw the Argentina midfielder lunge into his opponent.
Piquionne doubled the lead with eight minutes remaining, latching on to Boateng’s cross, spinning around Jamie Carragher and finishing crisply.