With holders Liverpool out of the equation - after their defeat to Atletico Madrid - City appear to be the strongest club left in the competition, but must survive a tricky assignment with serial winners Real Madrid if they are to win the trophy that has eluded them.
The English side entertain the 13-time European champions behind closed doors on Saturday morning (AEST), almost six months after prevailing 2-1 at the Bernabeu in the first leg of the round of 16 tie.
A lot has happened since February 27, when late goals from Gabriel Jesus and De Bruyne overturned an opener from Isco to put Pep Guardiola's team in the box seat for a spot in the quarter-finals.
City finished well behind Liverpool in the race for the Premier League, while Madrid edged past Barcelona to snare Spain's La Liga title.
City would have been bitterly disappointed with their meek surrender of the domestic title and will see the Champions League as a chance to redeem themselves and finish the season with a flourish.
They also regard the elite competition as another opportunity to crown their wealthy owners' massive investment that was designed to make City the best of the best.
Depending on how you look at it, City are technically the world's richest club, due to the City Football Group's financial might, and the fact they have yet to become kings of Europe must rankle with the owners.
Europe is where true greatness is measured.
City have so far failed in their attempts to translate their domestic bliss into European euphoria for reasons ranging from a lack of genuine quality in key positions to a suspect temperament.
None of these factors were evident in this season's campaign as City comfortably won their group featuring Atalanta, Shakhtar Donetsk and Dinamo Zagreb before winning in style in Madrid, which is never an easy place to go to.
Even in England, where they trailed Liverpool all season, they showed enough to suggest that on their day and when the inimitable De Bruyne is on fire, they can produce sublime football and beat anyone.
Germany's Bayern Munich, who are seen as City's stiffest challengers, are just about home and hosed after defeating Chelsea 3-0 in the first leg at Stamford Bridge.
Nobody in their right mind would give the Londoners any more than a token chance of turning the tables on Bayern and making the biggest comeback since Lazarus.
Ace striker Robert Lewandowski played a huge part in Bayern's ninth straight Bundesliga title by scoring 34 goals.
Barcelona and Juventus, who faced each other in the 2015 final, are usually strong contenders for outright victory - but they have seen better days.
Major flaws have emerged in the last two seasons, particularly in Barca's defence and in Juve's midfield, that have proved costly.
The two giants from La Liga and Serie A will have their work cut out to overcome Napoli and Olympique Lyonnais respectively. The two ties are still wide open.
Lionel Messi and Cristiano Ronaldo have effectively carried Barca and Juve all season with many goals, but they can't do it on their own and you feel that the Champions League might just be a bridge too far for them this season.
Superstars they are but supermen they are not, after all.
The quarter-finals, semi-finals and final will take place in a hub in Lisbon's two main stadiums that are home to Benfica and Sporting.
The single-match format of the competition should give all teams an even chance.
Which is why clubs like rookies Atalanta and Red Bull Leipzig will fancy their chances of beating the far more experienced Paris St-Germain and Atletico Madrid.
In a one-off 'cup tie' anything can happen and coaches Thomas Tuchel of PSG and Atleti's Diego Simeone have to get it right on the night because there will be no second chance this time.
Man City may or may not land the elusive prize that matters most to clubs of their stature, but somehow the odds seem to be stacked in their favour.
THE ROAD TO THE FINAL
Round of 16
Aug 8: Man City v Real Madrid (2-1)
Aug 8: Juventus v Lyon (0-1)
Aug 9: Bayern v Chelsea (3-0)
Aug 9: Barcelona v Napoli (1-1)
Quarter-finals
Aug 13: (1) Atalanta v Paris St-Germain
Aug 14: (2) RB Leipzig v Atletico Madrid
Aug 15: (3) Barcelona/Napoli v Bayern/Chelsea
Aug 16: (4) Man City/Real Madrid v Juventus/Lyon
Semi-finals
Aug 19: Winners 1 v Winners 2
Aug 20: Winners 3 v Winners 4
Final
24 Aug: Estadio da Luz, Lisbon
