De Bruyne, who has been sidelined with a hamstring injury, came on in the second half as two goals from Phil Foden as well as strikes by Julian Alvarez, Jeremy Doku and a Ben Jackson own goal sent Pep Guardiola's side into the fourth round.
Manchester City won the trophy last year as part of an epic Treble-winning season and few gave Huddersfield - 21st in the Championship - much chance of causing an upset.
The visitors kept out their opponents for 33 minutes with some determined defending but City always looked capable of going through the gears and they opened the scoring when Foden drove home from inside the box after Alvarez's shot was blocked.
Alvarez then got on the scoresheet after the hosts carved open the Huddersfield defence with some intricate passing before the Argentina forward's deft finish rolled into the net.
A dinked pass intended for De Bruyne from the impressive Oscar Bobb then deflected off Jackson and looped into the net early in the second half before Foden smashed in his second.
Doku, also making his return from injury, got the hosts' fifth when he swept home with Huddersfield goalkeeper Lee Nicholls stranded.
There were chants of "we want 10" from some home supporters, with older fans perhaps reminiscing about the 10-1 win City enjoyed against Huddersfield in 1987.
That never looked likely and, to the Terriers' credit, they fought hard and defended well at times against a City side capable of tearing apart almost any team at any level.
Manchester City won an incredible five trophies last year but the most successful sides rarely rest on their laurels and they will be determined to enjoy success again this year.
They took the first step towards defending the FA Cup with this ultimately routine victory - but perhaps just as important as avoiding an early upset was the return of De Bruyne.
Guardiola knows he is going to need his best players fit if they are to fight on multiple fronts and there is no doubt they have missed De Bruyne in the first half of the season.
His entry to the game was greeted by a standing ovation from the home fans, who also chanted his name, and the Belgium playmaker served a reminder of his ability with an assist for Doku's goal.
De Bruyne had made just one Premier League appearance before he was injured but he came through his 33-minute appearance unscathed to hand Guardiola a welcome boost heading into the second half of the campaign.
-- Courtesy of BBC Sport