The Reds can stretch their unbeaten run in the league to four following their late 3-2 victory over Tottenham Hotspur last Sunday.
The Merseyside outfit are seven points adrift of a Champions League spot having played one game more than their rivals, but a sixth-place finish, which would ensure Europa League football, is on the cards.
In contrast, the Saints are just four points away from getting relegated back to the Championship with nine games left to play in the campaign.
Liverpool haven't visited St Mary's since 2005, when they lost 2-0, but they were able to secure a slender 1-0 win over the Saints at Anfield in December.
Southampton boss Mauricio Pochettino is expected to opt for Liverpool fan Rickie Lambert to provide goal threat up front, while Reds manager Brendan Rodgers should welcome back goalkeeper Pepe Reina from injury.
Possible starting lineups
Southampton: Boruc; Yoshida, Fonte, Hooiveld, Shaw; Schneiderlin, Rodriguez; Cork, Ramirez, Lallana; Lambert
Liverpool: Reina; Johnson, Carragher, Agger, Enrique; Lucas, Gerrard; Downing, Coutinho, Suarez; Sturridge
Sports Mole says: 1-2