While the La Liga outfit have been largely impressive this season, Milan are languishing in ninth in the Serie A.
Ahead of his side's trip to the San Siro on Wednesday, Simeone said he expected to see plenty of goals as the teams target a quarter-final spot.
"I don't think this game will be an easy one," the Argentine said.
"I imagine a game with chances for both sides, an open one, according to what I've seen from them and also to how we normally perform.
"I'm very bad at predicting scores, I prefer to leave it aside, but undoubtedly this first leg of the tie will be key ahead of the second.
"The one getting the advantage tomorrow will be in a good position to reach the quarter-finals."
Milan are rebuilding under Clarence Seedorf and are capable of anything with Italy international Mario Balotelli up front.
Atletico have plenty of attacking talent of their own with Diego Costa and David Villa, and their form this season – which sees them sitting third in the league and equal on points with Barcelona and Real Madrid – has them favourites.
That matters little to Simeone.
"I'm not concerned about who's the favourite in this tie because we don't believe in that," Simeone said.
"Favouritism has to be shown on the pitch. We need to perform well, trying to play the whole tie focused.
"Italian sides live from impulses because they have players to do so. So our chances in this tie will be up to our concentration, determination and intensity."
