The Citizens failed to break their newly-promoted opponents down in the opening three-quarters of the match, but a Sergio Aguero strike and Lewis Dunk own goal in the remainder got them over the line.
Brighton had a good chance to open the scoring through Dunk earlier in the half, only for opposition keeper Ederson to redeem himself after initially making an error, and that would prove a big moment as the hosts were denied a dream result on their return to the top flight.
City saw nearly 80% of the ball in the opening 45 minutes but struggled to do a lot with it, though they did have plenty of joy down the Brighton left early on.
The Citizens were fluid in attack, particularly when Gabriel Jesus was near the ball, and the Brazilian thought that he had opened the scoring just short of the half-hour mark.
Referee Michael Oliver did well to spot that Jesus used his hand to help De Bruyne's pass over the line, however, ruling out the goal and - perhaps harshly considering he knew little about it - booking the young forward in the aftermath.
City did manage to up things slightly as the half wore on, seeing Jesus's close-range header from Sergio Aguero's lofted cross kept out by Ryan, before the follow-up attempt clipped the outside of the post.
Brighton barely got out of their own half in the first half but they did register one attempt before the interval, as Pascal Gross headed a free kick for Ederson to pluck out of the air from under his crossbar.
There was a sign that Aguero was not quite at the races 10 minutes into the second half when, following a Dunk error, the striker fired horribly wide with just Ryan left to beat.
Duffy was to be denied by Ederson two minutes later, with the newbie keeper redeeming himself after initially flapping at a cross to give the Albion man a clean shot at goal.
Momentum was soon wrested back by the Citizens, though, and they finally had a breakthrough goal 70 minutes in when Aguero tucked past Ryan after Dale Stephens was caught in possession by De Bruyne.
It did not take too long for the second to arrive, this time after Dunk put into his own net when attempting to clear Fernandinho's cross but only managing to beat his own keeper from close range - the seventh Premier League debutant to score an own goal.
Brighton struggled to really create anything in the remainder of the match, meaning that they will have to wait for their first victory back in the top flight after a 34-year absence.