After taking a measly five points from their opening four games, Atletico appear to have turned a corner with convincing wins over Getafe and Huesca, moving to within two points of front-runners Barcelona and Real Madrid.
Victory on Saturday would lift them above their bitter city rivals and Real's flying start under coach Julen Lopetegui was derailed by a humiliating 3-0 defeat by Sevilla.
Atletico have bragging rights from the last time the two teams met in August, winning a thrilling UEFA Super Cup match 4-2 in extra-time to end their European hoodoo against Real, who beat them in the 2014 and 2016 Champions League finals.
They appeared to suffer a hangover from that win following draws against Valencia and Eibar and a defeat by Celta Vigo but looked back to their rugged best in their 2-0 win over Getafe and 3-0 stroll against Huesca.
"I'm happy because the team have started to look like the Atletico we all want to be," Atletico winger Angel Correa said after beating Huesca.
"It's going to be an intense derby which I'm sure will be decided by the thinnest of margins."
Despite Real's dominance in most European matches with Atletico, Simeone's side have a remarkable record at the Santiago Bernabeu, where they have not lost a league game since December, 2012, when Jose Mourinho was in charge.
Real will be without key playmaker Isco after he underwent surgery this week to treat an appendicitis while Marcelo is a doubt after hurting his calf against Sevilla.
Lopetegui may decide to recall Keylor Navas in goal after an unconvincing display against Sevilla from Thibaut Courtois, who spent three seasons on loan at Atletico and whose plaque at the club's Wanda Metropolitano stadium was vandalised following his move to Real from Chelsea in August.
The Real coach has admitted his side were outplayed against Sevilla.
"When we win a game we prepare for the next one naturally and we'll do the same after this defeat," Lopetegui said.
"These things happen in a league season and they happen to every team. In three days we have another demanding game and we're going to lift ourselves up quickly and prepare for the game with the maximum intensity."
(Reporting by Richard Martin, editing by Ed Osmond)
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