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.
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.
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 Wilfried Bony reacted quickly to the rebound and the ball was deflected in off Rami.
The second half was more subdued than the first 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.
MANCHESTER CITY: Hart, Zabaleta (Kolarov 60), Otamendi, Mangala, Sagna, Jesus Navas, Toure, Fernandinho, De Bruyne (Kompany 90), Sterling, Bony (Fernando 76). Subs not used: Caballero, Demichelis, Barker, Glendon.
SEVILLA: Sergio Rico, Coke (Mariano 84), Rami, Kolodzieczak, Tremoulinas, Vitolo, Iborra, Krychowiak, Konoplyanka (Nzonzi 78), Banega (Krohn-Dehli 66), Gameiro. Subs not used: Soria, Reyes, Andreolli, Llorente.