The centre-back turned out 80 times for the St Mary's side before his £75 million transfer to the Reds last month.
Fellow former Saint Dejan Lovren switches to the bench in one of three changes from Jurgen Klopp.
The captain’s workload is being managed, having recently returned from a month out with an injury, while the vice-skipper is named in reserve.
Emre Can, as the longest-serving player in the XI, will wear the armband at St Mary’s as Liverpool look to regain third place.
Adam Lallana, who played 265 times for Saints, is on the bench after nursing a muscle issue. He last featured in the 1-0 defeat at Swansea City on January 22.
Hosts Southampton have made just one change to the starting XI that won 3-2 at West Bromwich Albion last week, with Pierre-Emile Hojbjerg replacing Sofiane Boufal in midfield.
Liverpool starting XI: Karius, Alexander-Arnold, Matip, Van Dijk, Robertson, Can, Wijnaldum, Oxlade-Chamberlain, Salah, Mane, Firmino
Liverpool subs: Mignolet, Lovren, Moreno, Milner, Lallana, Ings, Solanke.
Southampton XI: McCarthy, Cedric, Stephens, Hoedt, Bertrand, Romeu, Lemina, Hojbjerg, Ward-Prowse, Tadic, Carillo.
Southampton subs: Forster, Yoshida, Davis, Boufal, Redmond, Long, Gabbiadini.