Jurgen Klopp makes six changes in total as Andy Robertson, Jordan Henderson and Fabinho all return for Liverpool.
Robertson has been nursing a minor injury of late after suffering some tightness in a hamstring during Scotland's win over Denmark during the international break and was only a second-half substitute in Wednesday's 2-0 victory against Porto.
The Scottish skipper is back in Liverpool's defence, however, alongside Virgil van Dijk and Trent Alexander-Arnold as Ibrahima Konate keeps his place from the midweek Champions League triumph.
As a result Joel Matip, Kostas Tsimikas and Neco Williams all drop to the bench for the visit of Southampton.
READ MORE: Liverpool told to replace Mohamed Salah and Sadio Mane with two players
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It's only the third time Henderson has started in the same midfield alongside Fabinho and Thiago Alcantara as the captain makes his return to the XI after an injury himself on England duty earlier this month.
Diogo Jota comes back into the side in place of Takumi Minamino as the Portugal international leads the line with Sadio Mane and Mohamed Salah either side of him.
Tyler Morton's reward for his impressive Champions League debut on Wednesday is a place on the Liverpool bench as the Reds aim to go second in the Premier League.
Liverpool: Alisson; Alexander-Arnold, Konate, Van Dijk, Robertson; Fabinho, Thiago, Henderson; Salah, Jota, Mane.
Subs: Kelleher, Milner, Minamino, Oxlade-Chamberlain, Tsimikas, Origi, Matip, Williams, Morton.
Southampton: McCarthy; Bednarek, Lyanco, Salisu; Livramento, Ward-Prowse, Romeu, Perraud; Broja, Adams, A.Armstrong.
