The Atletico coach is expecting a tough Copa del Rey final against the deposed Spanish champion and says his side has been working on its approach.
The two capital clubs meet each other at the Santiago Bernabeu looking to scoop silverware but the Argentine is hoping his side can defy the odds.
"We can't afford to make any mistakes against them. They're better, without doubt, but everything changes in one game; anything's possible," he said at a press conference. "We're a side who play with commitment and humility and in the world nowadays, where everything is tough, I'd compare us to the people out there. Everything is tough.
"Hopefully we can give hope to people, and with hard work, humility, teamwork and the possibilities we have we can compete with Real Madrid and succeed.
"It's about transmitting the good things, but today and tomorrow are special days for the players.
"The motivation only goes so far and over motivating the players is not good because you have to play first and then the rest comes: the rebellion, the fear... Because fear exists on both sides, and Madrid are no different.
"I'm expecting a game that will follow certain characteristics. Our rivals are quick and difficult to contain with three quarters of the pitch in front of them, but we're also dangerous playing in space.
"The team that successfully manages to link up between midfield and attack will be closer to victory. That's that way the game will go."
Atleti has not won against Real Madrid for 14 years and suffered a 2-1 home loss to its rival in La Liga recently, but Simeone says his side has been working hard.
"We've worked on how we can hurt them. We could've won the league game but we lost because of a counterattack," he said. "In this game the motivation is in each and every one of my players and they are all ready to win tomorrow."