The Argentina striker is still recovering in Barcelona after undergoing an operation on his meniscus.
He has been included in City’s squad for the latter stages of the competition, but will definitely miss the second leg of their round of 16 tie with Real.
Meanwhile, Aleksandar Zinchencko should come in at left-back with Benjamin Mendy suspended.
Pep Guardiola failed to offer any assurances Aguero would be able to play a part if City progress to the quarter-finals and beyond in Lisbon.
He said: “Right now I don’t know. He’s still in Barcelona. He’s getting better and everything is like we thought, but he’s still there. Hopefully he can come back and start training, but I don’t know.”
Aguero wasn’t even involved in the first leg in February as Guardiola opted to play with a false No9 and Gabriel Jesus in a wide role.
He could look to do the same again at the Etihad, but admits outthinking Zinedine Zidane is one of the toughest tasks in football.
He said: “It’s difficult to know - when you think you’ve one of his plans covered, he’ll hit you with another. It’s very difficult to analyse his tactics.
“A long time ago in the past we played the first leg. What we remember, we’ve put to good use. Since then we’ve watched all their games since lockdown, spoken of how we think they’ll approach it.
“We’ve talked of how we can hurt them, that’s what we have focussed on in the build-up to this game.
“Quite often managers plan for games, but the game speaks for itself. The way it develops dictates it.
“We want to impose our style on the game, whether that’s defending counter attacks - we want to take the game to areas where we can hurt them. Where our quality can stand out.”
Manchester City predicted XI to face Real Madrid (4-3-3): Ederson; Walker, Fernandinho, Laporte, Zinchenko; Gundogan, Rodri, Silva; Jesus, De Bruyne, Sterling