Madrid travel to the Etihad Stadium on Friday (07.08.20), trailing 2-1 from February's first leg, but Real have since sealed the La Liga title after overhauling Barcelona in the resumed campaign.
The French defender told UEFA: "Without fans, it will surely be different. We always want to win, we are Real Madrid. We're coming off a great streak of wins so you can imagine how much confidence we've gained.
"There are no matches just before, so we have time to prepare for the game. It will really be the best team on the day that goes through."
Varane believes Real's experience in the Champions League could be an important factor as they look to reach the quarter-finals, which will be held in Lisbon as part of the plans to complete the delayed competition.
The 27-year-old centre-back explained: "We have the experience of major events. So we approach with perhaps a little more serenity, but always the same determination. And above all, we know the pitfalls to avoid. This is a bit of the experience we have over the past few years."
City boss Pep Guardiola has also warned that Real are capable of turning the tie around.
The Spanish coach said: "We should not think too much about our advantage. If any team can turn it around, it is a great one like Madrid, as well as Barcelona or Bayern. They know these competitions and they know how to play in them. They are a very strong team and they have helped me be a better coach."