Mali international Djenepo missed the defeat at West Ham after being given compassionate leave after the death of his mother.
Striker Danny Ings is in contention to return to the starting line-up, but Stuart Armstrong is out following a concussion. Will Smallbone is laid low by illness and winger Nathan Redmond (hip) remains sidelined.
Newcastle head coach Steve Bruce will make a late check on full-back Javier Manquillo after he complained of soreness following two starts since his return from a hamstring injury.
Manquillo played the full 90 minutes against Burnley last Saturday and then in the FA Cup fifth round victory at West Brom in midweek having been out since New Year's Day.
Bruce left out Martin Dubravka, Federico Fernandez, Jonjo Shelvey, Isaac Hayden and Dwight Gayle at the Hawthorns, who will all hope to return, while defenders Ciaran Clark (ankle ligaments), Paul Dummett (hamstring), Jetro Willems (knee ligaments) and Emil Krafth (ankle) and striker Andy Carroll (hamstring) are still out.
Southampton provisional squad: McCarthy, Stephens, Bertrand, Bednarek, Ward-Prowse, Romeu, Boufal, Hojbjerg, Djenepo, Obafemi, Ings, Gunn, Vestergaard, Walker-Peters, Yoshida, Valery, Long, Adams
Newcastle provisional squad: Dubravka, Darlow, Yedlin, Rose, Lazaro, Manquillo, Lascelles, Fernandez, Schar, Lejeune, Bentaleb, Hayden, S. Longstaff, Shelvey, M. Longstaff, Ritchie, Allan, Saint-Maximin, Almiron, Joelinton, Gayle, Muto, Sorensen.