Smalling (leg) pulled out of England's squad after playing in a friendly defeat to Germany, while Jones sustained a toe problem in training that has left him battling to play any further part in United's season.
Mourinho is already without the injured Paul Pogba for Saturday's Premier League match against West Brom, as well as suspended duo Ander Herrera and Zlatan Ibrahimovic.
And losing his defensive duo in the international break has not improved Mourinho's mood, although he did concede that he may one day have a different view on the issue when he moves into international management.
"I am totally against the friendly matches," he said to Sky Sports.
"I think friendly matches for the national team only make sense before the final phases.
"A couple of weeks before the Euros or a couple of weeks before the World Cup makes sense. But mid-season friendly matches mixed with qualification matches, I don't think that makes sense.
"On top of that the matches are not really big matches so I am not a big fan. But I think one day I will be there so I cannot be very critical.
"I don't know how but both central defenders got injured in the English camp even before the match.
"The match was on the Sunday against Lithuania and they were injured in the training session."
Mourinho feels United – who had 13 players on international duty – are at a disadvantage compared to Tony Pulis' men.
"If you compare our situation with our opponents - West Bromwich Albion only had one player on international duty. They had time to work, time to rest and prepare. It is going to be hard."
United - unbeaten in 18 league matches - are fifth in the table, four points behind Liverpool above them with two games in hand.