Van der Poel took the initiative in the latter stages of the ninth Tour de France stage, which was shortened due to the heatwave hitting France, attacking Mont Bessou at high speeds before beating Tobias Johannessen, Tom Pidcock, and Alex Baudin in the final sprint in Ussel.
Reigning champion Tadej Pogacar came home in the chasing peloton six seconds behind the winner to maintain his lead in the overall standings ahead of Monday's first rest day.
The four-time champion leads two-time winner Jonas Vingegaard by 2.42 minutes with Mexican Isaac del Toro a further 45 seconds back.
Van der Poel, a three-time winner of both the Tour of Flanders and Paris-Roubaix - the two most important one-day cobbled classics - had previously won Tour stages in 2021 and 2025.
This stage was shortened by around 30km due to a "red alert" weather warning in the central Correze region.
Temperatures once again reached close to 40C, although in parts of the stage it was nearer 30C.
There was a furious battle from the beginning of the 154.6km run from Malemort to Ussel to make it into the day's breakaway.
It was not until about halfway through the stage that an eight-man breakaway finally went clear on the steep 3.8km-long Suc au May climb.
The group never eked out a lead of more than a minute and a half, but they worked well together.
Van der Poel then attacked out of that group with 25km left on the final categorised climb of the day, the 900-metre-long and equally steep Mont Bessou.
Only Norwegian Johannessen, Frenchman Alex Baudin and Briton Pidcock were able to follow, and then it was a full-throttle charge to the finish line with a 50-second lead over the significantly reduced peloton.
The breakaway riders had plenty in the bag and even slowed down in the final kilometre in a cat-and-mouse game before the final sprint.
But when Van der Poel launched, it was clear he would be too strong for the others.