It's the first time in almost 14 years that Atletico takes on its illustrious neighbour with more points in La Liga - it is second with an eight-point lead over a stuttering Real, which was beaten again last weekend by Real Betis.
Despite winning the league last season, Mourinho is coming under fire from a demanding Madrid media who are speculating whether he will be still at the helm next summer.
The Portuguese flatly denied he is feeling the strain.
"I have perfect health and I am working as I have done for many years. My relationship with the players and the club is like it has always been," he said.
"This is not a courtroom but a press conference. I am just an employee of the club and it is they who decide if they are happy with what they have but I have a very, very, very good relationship with the president and the board."
Mourinho also had the backing of captain Iker Casillas who played down whistles that have been heard recently at the Bernabeu for the coach.
"Only a few months ago the shouts were applause and praise that we had won the league but in football memories are very short," Casillas said.
"'Mou' led the team to the title with a record number of points and goals. We should remember the good moments and look to continue the project."
Atletico's fine start to the campaign is partly due to the form of Radamel Falcao who has hit 14 goals in 13 games and he is now geared up for the derby.
"I don't feel as much pressure as motivation. We play a great side and it will be a high-tempo match but we will go out looking to win," Falcao said.
Barcelona takes on Athletic Bilbao aiming to maintain its prolific start, which has seen it only drop two points - in the Clasico against Real Madrid.
Lionel Messi has hit 19 goals in the league and is only three away now from Germany legend Gerd Muller's record of 85 in a calendar year.
"Messi is the best player in the world but there are other footballers with great qualities like Xavi Hernandez and Andres Iniesta who are not far behind," said midfielder Thiago Alcantara.
Malaga responded to a dip in form with a convincing 4-0 win over Valencia last weekend and faces Getafe, while Real Betis, which is level with it on 22 points, is away at Deportivo la Coruna.
At the other end of the table Javier Aguirre is preparing for his first league game at the helm of Espanyol against Granada after Mauricio Pochettino was sacked. Osasuna takes on Rayo Vallecano.
Levante looks to respond to its 4-0 defeat by Barcelona away to Celta Vigo and Valencia hopes to maintain its strong home record against Real Sociedad.
Elsewhere, Mallorca plays Zaragoza and Sevilla entertains Valladolid.