Davide Formolo (Bora-Hangsgrohe) took second, while his teammate Maximilian Schachmann completed the podium after 256km.
Astana’s Fuglsang, who won the first Monument of his career, rode solo from the 11km remaining mark after dropping Michael Woods (EF Education First Pro Cycling) and Formolo.
He was chased by the latter, who was 25 seconds down on him.
Fuglsang proved too strong for Formolo and the attacking groups that emerged from the peloton, which were 50 seconds behind him.
The final kilometre was a victory parade for the 34-year-old as he enjoyed claiming his big classics win.
Fuglsang said on the final climb he had his team leaving him in the perfect position.
“In the important moment they were there and they did an amazing job.”
He added that it was “an amazing feeling” to win.
“I’m happy that my wife is right [about being able to win] and I will always listen to her from now on, I promise.”
Other big news from this year’s race was four-time winner Alejandro Valverde (Movistar) abandoning the race.
This was the first time since 1992 that the finish of the Belgian race returned to the city centre, which was set on the Boulevard d’Avroy.