The Dutchman closed down a late attack from Dylan Teuns and Gonzalo Serrano before springing from the saddle out of the final bend and crossing the line with head in his handlebars, such was his exhaustion.
Biniam Girmay, whose Intermarché-Wanty-Gobert teammates had dominated much of the 2.2km final climb to the Citadel, came back at Van der Poel but had to settle for second in the pair's latest battle.
Serrano, who sat on Teuns' wheel when the Belgian attacked inside the final kilometre, sprinted to third place, with Teuns fourth.
"This finish is honest, I think. The strongest normally wins on a finish like that and I'm happy to be first," Van der Poel said.
But the Dutchman suggested his victory came as something of a surprise, revealing he struggled with the wet conditions and had intended to lead out teammate Jasper Philipsen, who could only manage sixth place.
"I didn't feel very very good, to be honest. I said to Jasper that I'd do the lead-out for him, but I think he didn't feel great either. On the final bend, I just did my sprint, I didn't know if they he was still in my wheel, but I still had the strength to go to the line, and it was a nice victory for the team."
While Alpecin-Deceuninck were prominent throughout, it was Girmay's teammates who dominated the twisting, cobbled final climb, until Teuns threw their train off track with a strong attack on the steepest section just inside the final kilometre.
Van der Poel waited patiently as Girmay's last man Loic Vliegen ground out the last of his reserves, before pulling them back just ahead of a 90-degree left-hand bend with 200 metres to go. Once through it, he rose from the saddle and burst through to the front, managing to hold off Girmay in a gruelling slow-speed sprint.
Van der Poel had barely raced since putting an end to an abject Tour de France after 10 stages, but his victory on Wednesday will enhance his status ahead of the Worlds road race in Australia on September 25.
The Dutchman returned to racing at the Druivenkoers-Overijse towards the end of August and while he did win a pair of Belgian kermesse events in the meantime, he now has his first road victory since May to take onto the flight to Australia.
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