The Corendon-Circus rider beat Anthony Turgis (Direct Energie) and Bob Jungels (Deceuninck Quick-Step) into second and third respectively after 183km.
With 65km remaining, Dries De Bondt (Corendon-Circus) attacked off the front of the peloton and started chasing the breakaway group, which consisted of Jonas Koch (CCC), Nelson Oliveira (Movistar), Ramon Sinkeldam (Groupama-FDJ), Zhandos Bizjigitov (Astana), Lukas Pöstlberger (Bora-Hansgrohe), Michael Hepburn (Mitchelton-Scott), Kris Boeckmans (Vital Concept-B&B Hotels) and Mihkel Räim (Israel Cycling Academy).
The breakaway had a two minutes and 26 seconds gap on the third climb of the day.
De Bondt was then joined by four fellow chasers, who were Van der Poel, Kasper Asgreen (Deceuninck/QuickStep), Ivan Garcia Cortina (Bahrain-Merida) and Turgis.
With 50km to the finish, Oliveira decided to go alone and created a 20 seconds gap as he made his way up Berg ten Houte.
Lotto–Soudal’s Tiesj Benoot attacked and pulled out a gap taking some riders with him, including defending champion Yves Lampaert (Deceuninck-Quick-Step).
Benoot’s move was then reeled back in by what was the remainder of the peloton.
With 44km remaining the nine-men chasing group that was 55 seconds behind Oliveira included Koch, Sinkeldam, Bizjigitov, Pöstlberger, Hepburn, Boeckmans, Turgis, Cortina and Van der Poel.
Shortly afterwards the chase group was 36 seconds behind Oliveira, while the peloton was one minute and 17 seconds behind.
When riders reached the Knokteberg, Pöstlberger attacked and caught Oliveira with 31km to go.
The chasing group behind them consisted of Benoot, Jungels, Van der Poel and Turgis.
With 27km remaining Oliveira suffered a mechanical and left Pöstlberger on his own after the former was passed by the chasing group.
Oliveira was then brought back by the peloton as Pöstlberger was caught by the Benoot group, who hit the Varentstraat sector of cobbles.
At this point there were two main groups on the road, which were the leading five-men group followed by the peloton with a 20 seconds gap between them.
With 17km remaining the leaders had a 48 seconds gap to the peloton, with Benoot pushing the pace.
At the 3km to go mark the five riders were still fighting it out between themselves.
Turgis attacked with 500m left, but Van der Poel passed him and took the win.