It is a match City must win to retain any hope of qualifying for the knockout stages from Group D.
Ronaldo, 27, is at the height of his powers and has scored a remarkable 165 goals in 162 appearances for Real, including the late winner when they met City at the Bernabeu in September.
Mancini is well aware of his threat, even without taking into account any extra incentive from playing back in Manchester.
Mancini said: "I think (it is) not only tomorrow night - I think Ronaldo has a big impact on every game.
"One player that scores every game, one or two goals, is an incredible player.
"For this reason we should have more attention on him because he is a player that can change the game."
City have collected just two points from their first four matches in the competition and are almost out of the reckoning.
Real will have plenty of reason to push for a result themselves as they trail group leaders Borussia Dortmund by a point and must shake off any late charge from Ajax or City.
City striker Carlos Tevez knows all about Ronaldo having played alongside him at Old Trafford.
Tevez said: "Cristiano is one of the best players in the world and he will play in this game the way he always has done.
"He does not seem to feel pressure, and there will be no added pressure just because he is back in Manchester.
"Once he gets a chance to face up to you and run at you with the ball he is very, very dangerous and he strikes the ball well too."
Tevez, 28, is well placed to enter the discussion as he is also an international team-mate of Messi.
He said: "I think it is only right if Cristiano does believe he is the best in the world.
"Any guy who gets 37 to 40 goals a season has a right to believe that, and is one of the best in the world, but if you push me I am always going to go on the side of Messi."
Mancini said: "It is my opinion that Real Madrid is the best team in the world - with Barca - and when you play against Real, you play against 11 top players and we should pay attention to all the players because they can score with top players.
"It is clear we should pay more attention in some situations but we should play our football.
"Football is fantastic because if you play against a top team like Barca and Real Madrid and you play well, you can win."
A controversial 2-2 draw with Ajax in their last game all but condemned City to a premature exit from the competition for a second successive season. Even if they beat Real and Dortmund in their final matches they may not be able to progress.
Mancini wants to take this game in isolation as a visit from nine-times European champions Real still makes for a great occasion for City.
He said: "It was a difficult group when we started and now it is very difficult because we did some mistakes in the first two games.
"But we have another two important games and we want to play well.
"We don't have a lot of chance to go through but it is important for us to do a good job."
The pair have been perceived as rivals since Mourinho succeeded Mancini at Inter Milan in 2008.
Mancini said: "Congratulations to him. To do 100 caps in the Champions League at his age (49) is very important, but I think tomorrow is not Mourinho against Mancini but City against Real Madrid. The players are more important than us."
City should at least by buoyed by the 5-0 victory over Aston Villa last weekend which took them top of the Barclays Premier League.
"It is better to prepare for this game now we are on the top but tomorrow is a different competition," Mancini said.