A five-week stretch includes a two-legged clash against Real in the last 16 of Europe's elite club competition and another meeting with Barca in LaLiga, with Atletico trailing the two giants by a point at the top of the table in a heated title run.
"The key, the only way, is to look at each day match-by-match," Simeone told a press conference on Monday.
"We are excited, we want to compete, looking forward to facing each game in the best way possible and to achieve that we are focused solely on tomorrow's game.
"It's a very important match, but it doesn't end tomorrow, it's divided into two stages, one on their home court and one on ours. And we'll take the game where we think we can hurt them."
The return leg is on April 2nd at the Metropolitano.
Atletico will tackle Barca on Wednesday two months after their last visit in late December saw them fight back to beat Hansi Flick's side 2-1 in a thrilling LaLiga encounter.
Simeone said his side are ready to suffer in what he expects will be a battle against LaLiga's leaders.
"When you face big teams you know you have to be prepared to resist, to endure suffering," Simeone said.
"There will be good moments for each side and you need to take advantage of those. It happened in the 1-1 draw against Real Madrid, where there were moments when they were better than us and the other way around.
"We have a concrete idea and we'll work on it with the boys beforehand. We're up against an opponent that I really like the way they play. They have great attacking strength and we'll be looking to hurt them where we think we can."