City had looked to be labouring to another unconvincing result in the competition, with only an Adil Rami own goal after Yevhen Konoplyanka's earlier strike saving them from possible defeat at the Etihad Stadium.
But as the game moved into four minutes of added time, De Bruyne raced on to a Yaya Toure through-ball and guided a shot into the bottom corner.
The goal transformed the mood at a hitherto subdued ground, with the even later introduction of Vincent Kompany off the bench further lifting fans.
Manuel Pellegrini's decision to leave Kompany on the bench for a second successive game was one of the night's major talking points.
Pellegrini has not started his captain since expressing frustration at his recent appearance for Belgium after a spell out injured.
It was a decision that looked likely to backfire as City continued to look vulnerable in his absence and were regularly cut open by the Spaniards on a drizzly evening.
City did create numerous chances but lacked the composure of the visitors, who also hit the woodwork through Konoplyanka.
Some of City's better moments came early on and Jesus Navas, hoping to his mark against his home-town club, had the first opportunity of the night with a well-struck shot from distance.
De Bruyne then teed up Toure with a good ball into the box but the midfielder missed the ball and Bony's consequent effort lacked power
De Bruyne also shot across goal but, despite these chances, City spent most of the first half on the back foot.
Konoplyanka was the obvious dangerman and he smashed a free-kick against the post before Joe Hart saved Grzegorz Krychowiak's follow-up strike.
Konoplyanka saw another chance deflected wide and Krychowiak missed the target with a free header from one of several Sevilla corners.
City had to rely on counter-attacks and Navas might have done better with one opportunity in front of goal before Yaya Toure saw a shot deflected over.
The home defence was cut open time after time and it eventually caught up with them as Vitolo squared for Konoplyanka to fire home the opening goal after 30 minutes.
City did produce a good response and they levelled within six minutes
Toure drove to the byline and pulled the ball back across goal
Raheem Sterling's shot was saved but Bony reacted quickly to the rebound and the ball was deflected in off Rami.
But despite the leveller, City continued to look vulnerable with Vicente Iborra heading over a good chance before the break and Kevin Gameiro similarly wasting an even better chance after the restart.
The second half was more subdued than the first but Iborra sliced a volley wide and substitute Michael Krohn-Delhi also missed the target as Sevilla continued to carry the greater threat.
City's supporters were clearly anxious and it was Sevilla's who were the more vocal but the hosts roused themselves in the closing moments.
Toure forced a good save from Sergio Rico with 89 minutes on the clock and De Bruyne then had the final say.
TWEET OF THE MATCH
Super Kev does it again! A wonderful goal from @DeBruyneKev surely wins the game for City!! 2-1! #cityvsfc #mcfc
- The official Manchester City Twitter account on Kevin De Bruyne's later winner in the 2-1 victory over Sevilla
PLAYER RATINGS
Manchester City
Joe Hart: 6 (out of 10)
Bacary Sagna: 5
Eliaquim Mangala: 5
Nicolas Otamendi: 5
Pablo Zabaleta: 5
Fernandinho: 6
Yaya Toure: 7
Raheem Sterling: 6
Kevin de Bruyne: 8
Jesus Navas: 6
Wilfried Bony: 5
Subs
Aleksandar Kolarov: 6
Fernando: 6
Vincent Kompany: 5
Sevilla
Sergio Rico: 6
Benoit Tremoulinas: 6
Timothee Kolodziejczak: 6
Adil Rami: 6
Coke: 6
Grzegorz Krychowiak: 7
Vicente Iborra: 6
Yevhen Konoplyanka: 8
Ever Banega: 7
Vitolo: 7
Kevin Gameiro: 7
Subs
Michael Krohn-Delhi: 7
Steven Nzonzi: 6
Mariano Ferreira: 6
STAR MAN
Kevin De Bruyne
The Belgian seems to have produced nothing other than superb performances for City since his big-money arrival in August and this was another fine display
Although his side took a long time to get going here, he always looked like their main threat - and it was no surprise that it was he who delivered the winning goal in stoppage time with a cool finish.
MOMENT OF THE MATCH
Kevin De Bruyne's winner
De Bruyne once again showed why City were prepared to pay so much to acquire his services as he collected the ball from Yaya Toure and carved some space for himself before slotting into the corner to hand City a dramatic victory.
VIEW FROM THE BENCH
City boss Manuel Pellegrini opted to field the same first XI that started Saturday's 5-1 demolition of Bournemouth, which made sense from an attacking point of view but also meant Vincent Kompany was once more on the bench.
What followed for long periods was the likes of Raheem Sterling and Wilfried Bony struggling to spark the way they had at the weekend, while City's defence looked even more suspect than in recent unconvincing performances.
Sevilla, in a 4-2-3-1 formation, caused constant problems for their hosts going forward and were resolute at the back for the most part
City deserve credit for battling back to win - with some changes by Pellegrini in the second half paying off - but the visitors will feel hard done by leaving with nothing.
MOAN OF THE MATCH
For a long time the hosts looked in need of proper leadership on the field, and particularly in defence - yet captain and centre-back Kompany only got on the field in stoppage time
While Pellegrini will no doubt talk about a cautious approach fitness-wise, City fans may well argue a full run-out for the skipper might have led to a less nervy evening.
WHO'S UP NEXT?
Manchester United v Manchester City (Premier League, Sunday, October 25)
Source : PA
Source: PA