Atletico moved top of the Primera Division table following Sunday's 2-0 victory over Real Betis before Real Madrid suffered a 4-3 home defeat to title rivals Barcelona to leave just one point separating the top three.
Simeone's side claimed a 2-1 victory over Granada in the reverse fixture earlier this season and they hope to pass the 100-goal mark this season in Wednesday's match.
On Sunday, Brian Rodriguez saw red for rock-bottom Betis for his second bookable offence, and Atletico scored twice in the next 10 minutes through Gabi and Diego Costa.
Simeone told the club's official website: "Gabi's goal came and that gave us tranquility, with the sending-off it became much more difficult for Betis and we took advantage of that situation to win a very important match for us."
And it was fitting that the Clasico ended with a win for Barca, enabling Atletico to move top.
Simeone added: "(The win) shows the tranquility of depending on ourselves for everything."
With Barcelona taking on Celta Vigo, and Real Madrid travelling to Sevilla on Wednesday night, Atletico know they need to continued their good run to remain in the lead.
Portugal midfielder Tiago Mendes returns to the squad after sitting out the Betis match due to suspension, while Brazil defender Filipe Luis is banned after he was booked on Sunday.
Granada sit in 11th in the standings following Saturday's 1-0 victory over Elche and they are looking to build on their three-match unbeaten run at the Vicente Calderon.
Coach Lucas Alcaraz welcomes back striker Francisco Piti and on-loan Liverpool defender Tiago Ilori, who have been nursing muscle injuries, while goalkeeper Roberto Fernandez is doubtful after spraining his ankle against Elche.