Rose's team will arrive at the Etihad Stadium for the last 16 second leg tie with just 17 available outfield players.
Christopher Nkunku and Xaver Schlager are among the key absentees for the Bundesliga club, who held City to a 1-1 draw in the first leg last month.
Leipzig were already underdogs against the Premier League champions even without their injury woes and Rose knows they must be perfect to spring a major upset.
"We played against the opponent a few weeks ago and we know what to expect but it sounds easy in theory. In practice against City it is a different ball game," Rose told reporters on Monday.
"The first half in Leipzig was bad. Our defence wasn't too bad but we hardly had any possession, that was the main issue.
"We want to be more intensive when we defend, meaning we will have a bit more possession, but once we have the ball we need to be a bit more responsible as well.
"If we only press it will open spaces for them, but if we just defend and don't attack we will concede at some point.
"We need to find the right balance, we need a lot of confidence and courage, and we will need our best match this season."
There was one positive piece of fitness news for Rose, with Spain forward Dani Olmo expected to feature after returning from a six-week injury absence for the 3-0 victory over Borussia Monchengladbach at the weekend.
"Dani coped pretty well with the injury. He is still recovering but he will definitely be a factor in this game, for 25 or even 30 minutes," Rose said.
"Dani will not be the Dani that we know but he will be of benefit to us, so we are happy that he is coming back."
