The 36-year-old Swede played in the number 10 role against Burnley on Tuesday but was replaced at half-time with the visitors leading 2-0. His replacement Jesse Lingard scored the two goals which earned Jose Mourinho's side a point.
And Ibrahimovic has not been named among the 18-man squad for Southampton's visit, with Lingard returning to the starting XI as one of three changes. The others see Victor Lindelof and Henrikh Mkhitaryan replace Marcos Rojo and Marcus Rashford. For Mkhitaryan it is a first start in 13 games in all competitions, having last appeared in the starting XI away to Chelsea on November 5.
Rashford is among the substitutes, along with the returning Anthony Martial who missed the Burnley clash with a slight muscle injury.
Under-pressure Saints boss Mauricio Pellegrino is still without target man Charlie Austin due to a hamstring injury combined with a three-match ban for kicking Huddersfield Town goalkeeper Jonas Lossl in the face in their 1-1 draw at St Mary's last Saturday.
Man Utd: De Gea; Young, Lindelof, Jones, Shaw; Pogba, Matic; Mata, Mkhitaryan, Lingard; Lukaku.
Subs: Romero, Blind, Rojo, Tuanzebe, Herrera, Martial, Rashford.
Southampton: McCarthy; Stephens, Yoshida, Hoedt, McQueen; Hojbjerg, Romeu; Ward-Prowse, Tadic, Boufal; Long.
Subs: Davis, Lemina, Gabbiadini, Redmond, Pied, bednarek, Forster.