Harry Wilson stunned Belgium with a superbly-crafted 10th-minute goal, but the star-studded hosts were soon ahead as De Bruyne fired home from distance and then played a major part as Thorgan Hazard's header gave them the lead.
Romelu Lukaku sealed victory for Group E favourites Belgium with a 73rd-minute penalty after Chris Mepham had needlessly brought down Dries Mertens.
Without manager Ryan Giggs, who has denied an allegation of assault, Wales faced what is on paper the most difficult challenge in international football – an away game with Belgium.
The Red Devils top the FIFA world rankings and entered World Cup qualifying unbeaten in competitive home matches since losing to Germany in September 2010.
Belgium also had the incentive of avenging their Euro 2016 quarter-final loss to Wales, a defeat which cost Roberto Martinez's predecessor Marc Wilmots his job.
Seven players remained from that game in Lille – Thibaut Courtois, Thomas Meunier, Toby Alderweireld, De Bruyne and Lukaku for Belgium and Wales pair Joe Allen and Gareth Bale – as the two countries met for the sixth time in the last decade.
Wales were unbeaten in the last four meetings and caretaker boss Robert Page welcomed Allen back into the international fold.
The Stoke midfielder ruptured an Achilles tendon 12 months ago and had not played for Wales since November 2019.
Liverpool teenager Neco Williams also came into the side following November's Nations League win over Finland, while Belgium's major team news centred around Lukaku.
The former Manchester United striker had arrived late in camp following a coronavirus outbreak at his club Inter Milan. But Lukaku started and his presence encapsulated the size of the visitors' task with his 57 international goals from 89 games being one more than the entire Wales squad.
Both sides took the knee before kick-off and Wales suffered an early blow as Allen's international return lasted only seven minutes, an apparent hamstring injury ending his night prematurely.
But Wales were quickly ahead as a slick one-touch passing move opened up the Belgium defence. Bale fed the final pass into the stride of Wilson, who claimed his fifth international goal with aplomb.
Youri Tielemans' shot was deflected wide and Lukaku somehow steered De Bruyne's brilliant cross over the bar from two yards out as Belgium settled to their task.
De Bruyne continually drifted into dangerous positions and Wales were punished after 22 minutes when the Manchester City midfielder was allowed space to unleash a 25-yard shot, which flew in off a post.
Belgium continued to press and took the lead six minutes later as De Bruyne set up Meunier to cross from the right.
Connor Roberts slipped on the difficult surface and Hazard sent a powerful header past Danny Ward in the Wales goal.
Hazard sent another shot over and Wales were relieved to hear the half-time whistle still in the contest.
There was more intent about Wales after the interval as Bale almost tricked his way through a packed home defence before the Wales captain's audacious overhead kick fell wide.
Daniel James was also off-target twice as Belgium sat back with almost half an eye on Saturday's trip to the Czech Republic.
But the result was put beyond doubt as Lukaku's spot-kick confirmed Wales' first defeat in 12 competitive matches and left the Dragons playing catch-up in World Cup qualification.