Felix sustained a hamstring injury in the 2-1 win over Espanyol on Sunday and was substituted at halftime.
Felix was having his best season for Atletico since joining them from Benfica in the summer of 2019.
The 22-year-old has made 35 appearances across all competitions for Atletico this season, scoring 10 goals and providing six assists.
Atletico Madrid head into Wednesday's game against Granada fourth on the La Liga table with just six games left to play.
Ahead of the game, Simeone announced that Felix will play no part in the remainder of this season's games.
"We have lost them [Joao Felix and Lemar], and [Hector] Herrera and Jose [Gimenez] are waiting to join the group, we hope they do so after this match," Simeone told his pre-match press conference.
"We lost Joao, who was in a great moment, with games, playing in continuity, [it was going] very well for his growth and play, [and] Lemar always gives us something different, in that defence to attack transition.
"It's a shame. They are injuries that come to us at a bad time, but I have other boys waiting to play and everyone is up to the task of continuing to compete as we have been lately."
