"I am pretty sure he will play, but I don't like it when players are not 100 percent fit," Mourinho told a news conference Friday.
"If Cristiano had to play tomorrow he wouldn't because he is not fully fit, but I am sure he will play next Wednesday after training on Saturday, Sunday, Monday and Tuesday."
Ronaldo, 26, left the field in the 76th minute of Real's league encounter with Malaga on March 3 after suffering a muscular injury in his left thigh.
Mourinho is set to leave the striker on the sidelines this weekend when Real face Hercules in La Liga in the hope he can battle back to match fitness for Wednesday, when a place in the quarter-finals is at stake.
Lyon held Real to a 1-1 draw at the Stade Gerland last week, meaning there is everything to play for during the second leg at the Santiago Bernabeu stadium.
Nine-time winners Real have fallen at the last 16 stage in each of their last six seasons, and Lyon eliminated Real 2-1 at this stage of the competition last year.