With both players missing England's 2-0 World Cup qualifier victory over Lithuania, Mourinho questioned the need for friendlies during the domestic season.
"I am totally against the friendly matches," he told Sky Sports. "I think friendly matches for the national team only make sense before the final phases.
"But mid-season friendly matches mixed with qualification matches, I don't think that makes sense."
United will be without both defenders for Saturday's Premier League clash against West Bromwich Albion, while midfielder Paul Pogba and captain Wayne Rooney are also on the treatment table.
Leading scorer Zlatan Ibrahimovic and midfielder Ander Herrera will miss the weekend's game as they serve the final game of their suspensions.
With 13 United players involved in international games over the past week, Mourinho said his side were at a disadvantage against eighth-placed West Brom.
"If you compare our situation with our opponents, West Bromwich Albion, only one player on international duty," he added.
"They had time to work, time to rest and prepare. It's going to be hard."
United are fifth in the league, four points behind fourth-placed Liverpool with two games in hand.
(Reporting by Hardik Vyas in Bengaluru; Editing by Peter Rutherford)
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