Teams from the Premier League have only progressed beyond the last 16 on four occasions since Chelsea won the tournament in 2012.
Mourinho criticised organisers of England's top flight last season during United's gruelling run to a victorious Europa League final, accusing them of failing to protect their clubs competing in Europe.
Ahead of his side's first Champions League game of 2017-18 against Basel on Tuesday, the former Chelsea boss again highlighted a different approach to other major leagues that he believes puts English teams at a distinct disadvantage.
"The only thing I can say is that Real Madrid last year played the last month in La Liga with the second team," he said. "They could do it and they arrived at the Champions League final with a fresh team.
"For English teams, normally, that's impossible. There's no winter break, like in other countries, although I have to admit that I love the Christmas period in English football.
"But no complaining. We have a squad, if you see the players are tired then you have to play others."
Mourinho admits United are perhaps not at the level of certain elite Champions League sides given that they have only qualified for the tournament twice in the last four years.
However, he says he would gladly accept a repeat of his past meetings with Basel if it meant United reached the last 16.
"I think in the Champions League there are four or five teams with an incredible level, quality, experience, know-how, and that's what makes the difference," he said.
"We have to try to go to the last 16 and enjoy that special knockout phase with the best teams in Europe.
"We're strong, playing well and have confidence in ourselves," says Jose. "It's a difficult game tomorrow but we have the quality to win." pic.twitter.com/CO67X9OCfq— Manchester United (@ManUtd) September 11, 2017
"To be humble is to admit that the opponent has the same ambition we have, that they can come here like they did in the past and give Manchester United a bad taste.
"But we go into this match thinking we can win, we go to Moscow and to Lisbon thinking we can win. We consider that we can win every match and that's what we're going to try.
"I would perfectly accept what happened the last time I played them [in 2013]. I played and I lost the match in Basel and in London, but we qualified. For me, what matters is to qualify.
"I think we are strong, playing well, with confidence in ourselves."