Cristiano Ronaldo quit Real Madrid for Juventus in an €105m transfer this summer.
The Champions League winners have struggled under Julen Lopetegui in the early stages of the 2018/19 season.
It's Real Madrid's worst start a season since 2001 - while Juventus are enjoying their best ever start to a Serie A campaign.
Without their all-time record goalscorer, Real Madrid have managed just one goal in their last five outings in all competitions.
Speaking at a press conference on Monday, Isco was asked if Real Madrid are missing Ronaldo.
"We can't look for solutions in someone who isn't here," said Isco. "We can't be crying for someone who didn't want to be here."
Later on Monday, Ronaldo spoke to the press in Manchester ahead of his Champions League return to Old Trafford.
RONALDO RESPONDS
Pressed by a reporter, the 33-year-old Portuguese forward responded to Isco's comments.
"It's all right. You can not cry," said Ronaldo with a smirk, as per A Bola. "I do not have to talk about other clubs.
"Everyone knows the story I had at Real Madrid and what is important tomorrow's game [against Manchester United].
"It's not for me to talk about the crisis of others."
Ronaldo can't pretend that his former club aren't in a "crisis."
Real Madrid are currently 7th in La Liga and there are rumours that Lopetegui could be sacked just four months into his tenure.
However, Isco doesn't believe his new coach deserves to be fired.
"I do not believe that the press has the power to sack a Madrid coach," said the Spanish midfielder.
"The controversy that you want to create in the dressing room is not there. We trust in the staff that we have and in what we have done.
"The boss has all our confidence. It would be crazy [to sack him]. You have to let him work.
"If you sack the coach you have to sack us all because we are the ones on the field – this is something for everyone, not just the coach.
"Historically, people who criticise us come back later with their tail between their legs once we win Champions League."
Fair point, Isco.