Van Nistelrooy, who has been placed in charge following Erik ten Hag's departure, has made four changes to the side that started against West Ham United in the Premier League on Sunday afternoon.
Andre Onana, Noussair Mazraoui, Christian Eriksen and Rasmus Hojlund have dropped out, with Altay Bayindir, Victor Lindelof, Manuel Ugarte and Joshua Zirkzee coming in for starts.
Marcus Rashford and Alejandro Garnacho will again operate in the wide positions, while Casemiro keeps his spot in midfield.
There are also notable spots on the bench for youngsters Jayce Fitzgerald and Jack Fletcher.
As for Leicester, head coach Steve Cooper has made a number of changes to the side that started against Nottingham Forest in the Premier League last time out, including starts for Conor Coady, Jordan Ayew and Oliver Skipp.
The Foxes have a strong bench at Old Trafford, but there is no spot in the squad for Jamie Vardy, with Cooper deciding to shuffle his pack ahead of Leicester's next league game against Ipswich Town on Saturday afternoon.
Manchester United: Bayindir; Dalot, De Ligt, Lindelof, Martinez; Ugarte, Casemiro, Fernandes; Rashford, Zirkzee, Garnacho
Subs: Heaton, Amass, Evans, Mazraoui, Fitzgerald, J Fletcher, Amad, Hojlund, Wheatley
Leicester City: Ward; Justin, Coady, Okoli, Thomas; El Khannouss, Skipp, Soumare, McAteer; Ayew, De Cordova-Reid
Subs: Iversen, Ricardo, Vestergaard, Ndidi, Winks, Mavididi, Edouard, Alves, Buonanotte
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