The Citizens knocked out perennial winners Real Madrid over two legs in the last round, while Lyon stunned Italian champions Juventus to progress.
The winners of this match at the Estadio Jose Alvalade, which will be played over just one leg, will face either Bayern Munich in next week's semi-finals.
Given the unique nature of this season's Champions League, with the quarter-finals onwards being played out in Portugal over the course of a couple of weeks, City's focus is solely on this competition.
Pep Guardiola has previously joked that he would be nothing more than a "failure" if he fails to win the competition during his time with City, and on the face of it there is no better time to lift the famous trophy than this season.
After finishing second in the Premier League and exiting the FA Cup at the semi-final stage, Guardiola knows that there is even more weight on his shoulders to go all the way this time around.
The Citizens certainly have momentum on their side following their 4-2 aggregate victory over Madrid in the first knockout round, following up their 2-1 first-leg triumph with a win by the same scoreline in last Friday's return fixture.
City may have been helped by some shocking defending from the usually reliable Raphael Varane, but they took their chances when they arrived and were comfortable winners in the end.
That famous victory made it three wins in a row for EFL Cup winners City in all competitions, and six victories in their last seven, scoring 23 goals and conceding only four during that run.
It will all ultimately count for little if they fail to overcome Lyon, however, and Guardiola will need no reminding of his side's struggles against the Ligue 1 opposition when they met twice in last season's group stage.
Maxwel Cornet and Nabil Fekir were on target as Les Gones secured a 2-1 victory at the Etihad Stadium, followed up with a 2-2 draw in the reverse fixture - another match that saw Lyon dominate the midfield battle.
Guardiola has a habit of overthinking knockout ties, trying to get into the opposition's head with his team selection, and it may well be that he focuses closely on those two matches - even if there has been a small turnover of players at both clubs.
Lyon looked a little rusty against Juve last time out and that is not at all surprising given that it was just their second competitive game in five months, the other being a defeat to Paris Saint-Germain in the Coupe de Ligue final on July 31.
This will be Lyon's first appearance in the quarter-finals of the Champions League since 2009-10, and they have progressed from just one of their previous four games at this stage, eliminating Bordeaux in 2009-10.
City are competing at the last-eight stage for a fourth time in five seasons, meanwhile, but they have advanced from just one of those previous ties - knocking out PSG in 2015-16 - and will certainly not take anything for granted on Saturday.
Manchester City Champions League form: WDDWWW
Manchester City form (all competitions): WWLWWW
Lyon Champions League form: WLWDWL
Lyon form (all competitions): WWLLLL
Indeed, Jesus has been directly involved in more Champions League goals for City this season than any other player (nine – six goals and three assists).
In terms of Lyon, Moussa Dembele was left out for the second leg against Juve but will surely be brought back into the side on Saturday.
Memphis Depay scored in that most recent match and has now netted in six successive Champions League games, so he is nailed on to start in attack and is one to watch.
Former City defender Jason Denayer, who spent four years at the Etihad Stadium without getting a look-in, will start in what is likely to be a back three for the French side.
Manchester City possible starting lineup:
Ederson; Walker, Fernandinho, Laporte, Cancelo; De Bruyne, Rodrigo, Gundogan; Mahrez, Jesus, Sterling
Lyon possible starting lineup:
Lopes; Denayer, Marcelo, Marcal; Dubois, Caqueret, Guimaraes, Aouar, Cornet; Dembele, Depay
We say: Manchester City 2-0 Lyon
City and Lyon picked up impressive results in the last 16, knocking out Madrid and Juventus respectively. The French side cannot be written off, then, but they have lost four matches in a row either side of the coronavirus hiatus and finished seventh in the shortened Ligue 1 campaign, so we are backing Guardiola's side to progress to just a second semi-final.