The Dutch star broke clear just over a couple of kilometres into the 177km stage and held on in front all day to win by more than a minute.
The 2023 laureate will be one of the favourites next weekend for the World Championships in Montreal, where reigning champion Tadej Pogacar will be missing due to injury.
"That was not the plan before the start, but I found myself alone from the start of the race in fact, and I just rode my tempo the whole day," the 31-year-old said.
A six-man chase group closed to within 30 seconds of Van der Poel, but were caught themselves with 44km still to ride.
"At first I thought the chasers would catch up to me, but I just continued to ride at my power, and the gap grew out again, so at that point I decided to just go all-out until the finish," Van der Poel added.
He has made a habit of launching long-range solo breaks this season, but never this far from the finish line.
It was one of the longest solo breaks in cycling history, and the longest this century.
Italian Davide Piganzoli finished fourth on the stage to secure the overall victory.