Tedesco's tenure started with a 3-0 victory over Sweden in Euro 2024 qualifying on Saturday (AEDT), and Belgium, inspired by new captain De Bruyne, impressed again at RheinEnergieStadion.
Germany had no answer inside the first nine minutes in Cologne as De Bruyne teed up goals for Yannick Carrasco and Romelu Lukaku.
Niclas Fullkrug's 44th-minute penalty offered Hansi Flick's hosts hope, but De Bruyne's slick 78th-minute finish ensured another victory at the start of a promising era under Tedesco as Serge Gnabry's late reply counted for little.
Carrasco fired Belgium into a sixth-minute lead after cutting inside from De Bruyne's pinpoint pass before coolly blasting into the roof of the net.
Another delicate De Bruyne throughball teed up Belgium's second, Lukaku racing through and lofting over an onrushing Marc-Andre ter Stegen.
Dodi Lukebakio inexplicably dragged a glorious chance wide before Lukaku headed onto the crossbar from De Bruyne's corner, prompting Flick to make two 32nd-minute changes.
The injured Leon Goretzka and Florian Wirtz made way for Felix Nmecha and Emre Can, with Germany responding as Fullkrug converted his penalty after Lukaku was adjudged to have handled.
Germany ramped up the pressure after the interval as Gnabry smashed just wide before Timo Werner saw a strike ruled out for offside. Joshua Kimmich also went close with a whistling low strike.
But De Bruyne put the game out of reach, finishing into the bottom-right corner from Leandro Trossard's offload, making Gnabry's late strike from Kevin Schade's low cross – shortly after hitting the post – a mere consolation.