The capital-based club defeated AC Milan to reach the last eight of the Champions League on Tuesday and will hope to use that as momentum in the Liga title race.
The Rojiblancos made it into the Champions League quarterfinals for the first time since 1997 with a 5-1 aggregate victory over Milan on Tuesday, sealed by a 4-1 scoreline on the night, but must quickly turn their attention back to the Primera Division title race.
Simeone's charges currently sit second, three points adrift of city rival Real, having leapfrogged third-place Barcelona — now one point behind Atleti — last weekend.
It is Barca's neighbors who visit the Vicente Calderon on Saturday, but Atleti will be wary of Espanyol, as the Catalans are one of only four teams to have beaten them so far this season.
Goalkeeper Thibaut Courtois inadvertently put the ball in his own net as the Rojiblancos were upset 1-0 at the Estadi Cornella El Prat in October.
Dauntingly for this weekend's visitors, though, Atleti is yet to lose on home soil in the league this season, scoring 43 goals in just 14 matches, while Espanyol has claimed just three wins on the road. Diego Costa is second only to Cristiano Ronaldo in La Liga's scoring charts and found the net twice midweek.
Javier Manquillo looks set to be the only injury concern for either side, as the Atletico man continues his recovery from a fractured spine.