Julen Lopetegui's side lost the UEFA Super Cup to Atletico Madrid but have started La Liga in strong fashion, scoring 10 goals in their three consecutive victories.
Seven of those goals have been scored by Karim Benzema and Gareth Bale – two players often said to be marginalised during Ronaldo's time at the Santiago Bernabeu – while the Portugal star himself has gone three games without finding the net since moving to Juventus in a €112 million (£88m/$117m) deal.
Isco admits Madrid are coping well without the five-time Ballon d'Or winner but feels any team will eventually miss a forward of such quality.
"Cris is an extraordinary player," he told a news conference. "He guaranteed you 40 to 50 goals. But if we win, they'll say we don't miss him and if we don't win, they'll say we do.
"We're playing very well now; players who didn't score as many goals last year are now filling their boots. We don't miss him at the moment. I wish him all the best at Juve."
Isco is preparing for Spain's Nations League clash with England on Saturday, their first since Luis Enrique took over as head coach after the World Cup.
The Madrid playmaker has been encouraged by the first few training sessions under the former Barcelona boss, even though he has made few alterations to their approach.
"We knew him already. He has a lot of character. He's won many things," Isco said. "In the end, the philosophy and the idea are the same. He changes a few things, he has his way of seeing football, but it's similar.
"We have had a few training sessions with him, we have to adapt but we're very happy. We're very enthusiastic at this stage.
"Every game requires a way to play. If you play against 11 behind the ball, there isn't much more you can try. We haven't won with long balls. We have to improve, but we have to continue from this point."
Luis Enrique is said to have introduced a handful of new rules within the team camp, including banning mobile phones when the players are having dinner.
"It's important to have boundaries," Isco said. "The mobiles at dinner rule seems good to me. It will be good for us not to have them with us all the time. Sometimes, we're more aware of them than our team-mates."