After a week of positive injury updates, news of Joël Matip's adductor problem late on Friday night means that former Saints centre-back Lovren - who has not started since a woeful display in a hammering at Tottenham Hotspur last month - is recalled to the back-line.
Jürgen Klopp opts to restore the Croatian as opposed to moving Joe Gomez into centre-back, with the 20-year-old - who was Man of the Match on his first England start from a central position on Tuesday - on the bench. Trent Alexander-Arnold instead starts at right-back.
Philippe Coutinho also returns to the squad for the first time since Spurs, having missed all three of Liverpool's wins over Huddersfield Town, Maribor and West Ham United with an adductor issue.
He starts as one of three midfielders as Klopp reverts to a 4-3-3, with Sadio Mané joining Mohamed Salah and Roberto Firmino in the front three. This is the first time the attacking trio, and Coutinho, have started a league game together.
Mané returned from international duty with a minor recurrence of the hamstring strain that kept him out for five games last month, but has been passed fit to start.
Captain Jordan Henderson also returns from a thigh injury to replace Alex Oxlade-Chamberlain, who scored his first league goal last time out, joining Georginio Wijnaldum and Coutinho in the middle. Emre Can is dropped.
Midfielder Adam Lallana does not return to the bench against his former employers despite returning to full training this week from a thigh injury that has kept him out for the past three-and-a-half months.
Southampton are without summer signing Mario Lemina, one of their better performers in what has thus far been a mixed season, in midfield for the third successive match.
They make two changes from the side that lost 1-0 to Burnley with ex-Liverpool defender and first-team coach Mauricio Pellegrino looking for a performance to inject some belief into their campaign.
Shane Long replaces top goalscorer Manolo Gabbiadini as the sole striker in a 4-2-3-1 set-up wit Wesley Hoedt starting in central defence over Maya Yoshida, who is benched, despite missing international duty with the Netherlands with a knee problem.
Virgil van Dijk - a well-known Liverpool target throughout the summer transfer window - starts in the heart of defence alongside him.
The South Coast club are looking to become the first side since Nottingham Forest, 39 years ago, to keep clean sheets in five successive meetings against Liverpool - while they have never gone six games without defeat against the Reds.
Liverpool, meanwhile, look for three successive league wins for the first time in 2017 and have lost only two of their last 32 top-flight matches at Anfield - conceding only once in their last seven home games.
The game sees three ex-Southampton players in Liverpool's 18-man squad - Lovren, Mané and Oxlade-Chamberlain - with Lallana and Nathaniel Clyne the absentees.
Full confirmed line-ups
Liverpool starting XI: Mignolet; Alexander-Arnold, Lovren, Klavan, Moreno; Henderson, Coutinho, Wijnaldum; Mané, Firmino, Salah.
Southampton starting XI: Forster; Cédric Soares, Hoedt, van Dijk, Bertrand; Romeu, Davis; Tadić, Boufal, Redmond; Long.
Liverpool bench: Karius, Gomez, Milner, Oxlade-Chamberlain, Can, Sturridge, Solanke.
Southampton bench: McCarthy, Yoshida, Targett, Højbjerg, Ward-Prowse, Gabbiadini, Austin.