The prolific attacker picked up a hamstring problem earlier this month and Ancelotti confirmed on Tuesday he would not be fit to face Gerardo Martino's men in Valencia, where he scored the winning goal in the final of 2011.
While he admits the loss of Ronaldo is a blow, Santillana believes los Blancos have proven they can produce the goods without the 29-year-old - as they did in their 4-0 thrashing of Almeria at the weekend.
"Real Madrid have played and won without Ronaldo before. They have coped with his absence as a team," Santillana told Goal. "But there's no denying that he gives something extra to the team, just like Lionel Messi does to Barcelona.
"They have so much quality that they can win titles on their own and the rest of the team knows that. A team consists of 11 players, but fact remains that Ronaldo and Messi are the best in the world."
Santillana feels Madrid's strength in attack and Barca's defensive injury problems tips the Copa final in the capital club's favor, and the 61-year-old believes the club can dream of a possible treble should it triumph on Wednesday.
"Real Madrid are not inferior to anyone. Barcelona head into the game without a number of regulars in defense and on the back of some defeats, while Madrid are at their best in attack," he said. "Winning the treble will be more complicated than a month ago, but it's still possible. Atletico [Madrid] are a great team, but it will not be easy for them with both La Liga and the Champions League.
"I don't see any team that is better than Madrid. Everybody sees Bayern Munich as the favorites, but I can see Madrid beating them."