Vladimir Smicer was joined by Milan Baros and El-Hadji Diouf in attack, while Markus Babbel made his long-awaited return to competitive action, and Chris Kirkland replaced Jerzy Dudek in goal. Jon Otsemobor also made his first team debut.
Patrik Berger gave the Reds a lead just before half-time after his free kick was deflected into the Southampton goal by Michael Svensson. Southampton's Ecuadorian striker Agustin Delgado equalised on 55 minutes, but two minutes later the Reds were ahead again, with Diouf hitting the back of the net after a brilliant run from Baros.
The Czech striker then added his own name to the scoresheet with Liverpool's third barely three minutes later, sliding in from Berger's cross.
Liverpool: Kirkland, Vignal, Babbel, Biscan, Otsemobor, Smicer, Berger, Cheyrou, Gerrard, Baros, Diouf.
Subs: Heskey, Arphexad, Diao, Diomede, Traore.
Southampton: Niemi, Dodd, Bridge, Lundekvam, Michael Svensson, Delap, Oakley, Marsden, Telfer, Delgado, Beattie.
Subs: Williams, Kanchelskis, Pahars, Tessem, Blayney.
Referee: P Dowd (Staffordshire).