An impressive defensive performance, paired with Heung-Min Son's goal 12 minutes from time, saw Spurs to a 1-0 victory in the first leg last week in north London.
City's lack of an away goal could prove crucial in deciding the tie, which is sure to be tight.
Avoiding defeat at the Etihad Stadium will not be easy, but Mauricio Pochettino's side have the ability to cause an upset on Wednesday by knocking out one of the tournament favourites.
Date: Wednesday, April 17
Time: 8 p.m. BST, 3 p.m. ET
TV Info: BT Sport 2 (UK), TNT (U.S.)
Match Odds (via Caesars): Manchester City 31-100, Tottenham 35-4, draw 22-5
A quick look at the injury lists for both sides reveals Spurs are the team with the more significant absentees, most notably Harry Kane, the club's No. 1 marksman.
However, Tottenham actually have a fantastic record without the England international this season.
Kane was missing for four Premier League games with an ankle injury earlier this year, and Spurs won all four.
The same injury ruled the 25-year-old out of Tottenham's Champions League last-16 first leg against Borussia Dortmund on February 13, which they won 3-0.
Kane will be a big loss, but Spurs have other threats in attack. Son is in fine form with two goals and an assist in his last three appearances, and Lucas Moura will be high on confidence after netting a hat-trick against Huddersfield Town on Saturday:
Both could be effective on the counter-attack against City, who are likely to dominate possession and will need to take the game to Tottenham given they are trailing in the tie.
One of the main criticisms made of Pep Guardiola in last week's first leg was that he left Kevin De Bruyne on the bench until the 89th minute.
The City manager surely won't do the same thing again on Wednesday after the Belgian playmaker's fine performance against Crystal Palace on Sunday:
De Bruyne has the ability to render an entire defence useless with a swing of his boot, and he will be the man City look for to provide the creative spark to get them back into the tie.