The 28-year-old Spanish international had surgery last month and Mourinho told the club website (www.manutd.com) on Friday that he would not be fit until "late May."
The final Premier League games are scheduled for May 21, with the Europa League final, should United reach it, being played in Stockholm three days later.
The pairing of Eric Bailly and Marcos Rojo have been at the heart of the defence in the absence of the English duo and the Portuguese boss is concerned with their accumulation of fatigue before United host league leaders Chelsea on Sunday.
"There is nothing I can do (about the current defensive situation)," said Mourinho. "They (Bailly and Rojo) have to go until the limits.
"If we arrived in a situation in the Premier League... where mathematically the top four is not possible, then it's an easy decision... rest them and go with them in the Europa League - if we are still in the competition."
Fifth-placed United are four points behind Manchester City, with a game in hand, and need to finish in the top four or win the Europa League to qualify for the Champions League.
Mourinho, who led Chelsea to three league titles in two stints at Stamford Bridge, said he was impressed by their style of play under manager Antonio Conte.
"They (Chelsea) are top for some reasons - it's not just because they are fresh," he added. "It is also because they have individual quality... collective quality. They have a certain style of play. They stick to it."
United are on a 21-game unbeaten run in the league since losing 4-0 on Mourinho's return to Stamford Bridge in October. (Reporting by Hardik Vyas in Bengaluru; Editing by Ken Ferris)