Van der Poel (Alpecin–Deceuninck) was part of a seven-rider leading group that seized control with 50km of the 257km race remaining.
He then launched an attack on the Carrefour de l'Arbre cobbled section after John Degenkolb (34, Team DSM) crashed heavily and his main rival Wout van Aert (28, Jumbo-Visma) punctured.
His main rival Wout van Aert (Jumbo-Visma) went with him and it looked like being a straight fight for the title between the pair of them, only for Van Aert to puncture.
There was no stopping Van der Poel then as he surged away in the sunshine towards the finish at the iconic Velodrome Andre-Petrieux.
On the second of two laps around the circuit Van der Poel could afford to milk the cheers of the crowd as he crossed the line. In the battle for second place his team mate Jasper Philipsen edged out fellow Belgian Van Aert.
Philipsen and Van Aert finished 46 seconds in arrears.
Former road world champion Mads Pedersen was fourth with Stefan Kung fifth and Italian Filippo Ganna sixth.
Van der Poel's win took his Monument tally to three having won this year's Milan-San Remo in dominant fashion and also taking victory at last year's Tour of Flanders.
"I had one of my best days on the bike," he told Eurosport. "I felt really strong and tried to do a couple of attacks earlier but it was really hard to drop the guys.
"On the last sector, Degenkolb had a crash then I had to close a gap to Wout and I think he had a flat tyre. I found myself alone in front and just rode as hard as I could."
Van der Poel has some sympathy for Van Aert with whom, along with Tadej Pogacar, he shares a rivalry that is arguably one of the most exciting for many years in men's cycling.
"When I passed him, his pace was low. I knew he had problem, but didn't know it was a flat tyre. It's unfortunate, maybe we would have gone as two to the finish line," he said.
"It's unfortunate but it's part of the race. You need good luck and good legs and I had both today."
