Los Rojiblancos kept up the pressure on league leaders Barcelona by crushing Pepe Mel's side thanks to goals from Diego Costa, Gabi, 18-year-old Oliver Torres and a brace from David Villa.
However, Simeone's side will have had just three days to recover from their exertions when they take to the pitch of Los Carmenes and in his pre-match press conference, the coach admitted it would be tough for Atletico to repeat their weekend showing.
"It's not easy to keep playing with the intensity in which we have kept playing. The players are trying to recover in the best way possible against a team that will play with hope and enthusiasm," he said.
Leo Baptistao is still out with a sprained ankle, while Simeone ruled Arda Turan out of the game.
The Turkey midfielder is still suffering from muscle discomfort, which forced him to miss the Betis match, meaning Raul Garcia is likely to be recalled to the team, starting ahead of the youngster Torres.
Granada coach Lucas Alcaraz turned up the heat on Atletico in his pre-match press conference, commenting on Simeone's side's physical approach in matches.
He said: "Atletico are a team that are managing very well what they are trying to do. They play to the limits of the rules, and referees are permissive with them, like they are with all big teams, and they make things very difficult for their opponents."
When asked about his opposite number's comments, Simeone refused to take the bait, simply declaring: "I don't give my opinion on comments made by my counterparts, I respect them."
Alcaraz is without midfielder Dani Benitez and forward Piti, who are both injured.
Simeone was one of the notable absences from the shortlist for FIFA's Coach of the Year award, which was published earlier this week.
The Argentinian led Atletico to third place in the Primera Division last season as well as winning the Copa del Rey, and this term his side have won nine of their opening 10 league games, while maintaining a 100 per cent start in the Champions League.
However, Simeone insisted he was not surprised to have been left off the list.
He said: "I congratulate the 10 coaches that are on the list. I don't look for recognition, my only aim is to work with my team and do the best I can for my club."