Atletico go into Saturday's clash with Athletic Bilbao one point clear of Barcelona at the top of the league with just eight games remaining as they chase a first title since 1996.
Real Madrid sit two points further adrift after back-to-back losses, a record in contrast to their city neighbours who have won their last four league matches.
But Simeone maintains that the resources of the two teams below them still makes Atletico outsiders, and they also face the daunting prospect of a possible title decider against Barca on the final day of the campaign.
"Each match becomes long, hard and difficult," he told a press conference.
"The guys are making an incredible and marvellous effort. The season is enormous but it will be valued by how it ends.
"With eight games to go, the advantage is for those who have more resources. If we get to the final four or five rounds like this, we'll liven up a bit.
"We have worked very well keeping a solid base. A group of players have wanted to improve and grow, knowing their faults and strengthening their virtues.
"This shows us that believing in what one does and working little by little, humbly, we can compete."
Barcelona go into their derby clash against Espanyol rocked by the news that Victor Valdes has played his last game for the club.
The goalkeeper, who will leave the Nou Camp in the summer, tore his anterior cruciate ligament against Celta Vigo in midweek and will be out of action for at least six months.
Manager Gerardo Martino admitted that losing the veteran was a blow but is confident his side will cope after losing Ibrahim Afellay, Lionel Messi, Neymar, Jordi Alba and Carles Puyol for periods of time this term through injury.
"It's a very hard blow, but this team has lived blow to blow for a long time and we will move forward," Martino told a press conference.
"This point in the season I thought that everything that was going to happen to us had already happened."
Real will be looking to bounce back from their recent disappointments when they take on Rayo Vallecano.
Losses to Barca and Sevilla have put a huge dent in Los Blancos' title aspirations but playmaker Isco remains confident they can bounce back.
"We are Real Madrid and are obliged to pick ourselves up," he told realmadrid.com.
"There are eight games left and we are confident in our ability to turn this situation around. We have already done that more than once. We came back from six points behind so why wouldn't we be able to do that now?"
In Saturday's other game Celta Vigo host Sevilla looking for a win that could move them eight points clear of the relegation zone.
Real Valladolid host Almeria on Sunday while Real Sociedad travel to Osasuna, Elche make the trip to Villarreal and Valencia welcome Getafe.
The weekend's action is then rounded off on Monday night with Granada taking on Levante and Malaga travelling to Real Betis.