The Dutchman has been holding the fort until Ruben Amorim's arrival on Monday, and is looking to extend his unbeaten record into a fourth match.
Leicester City come to Old Trafford again, as they did for Ruud's opening game as interim head coach, in the Carabao Cup, with Premier League points at stake this time.
Van Nistelrooy has opted to make three changes to the XI on duty against PAOK in the Europa League on Thursday night.
Matthijs de Ligt and Lisandro Martinez are reinstated at centre-back, with Jonny Evans and Victor Lindelof moving to the bench.