Capitalising on strong teamwork from the Boels-Dolmans squad throughout the 151km over the Flemish hellingen, it was van der Breggen who launched a powerful attack over the top of the Kruisberg, staying clear to the finish.
"This is the big one," said van der Breggen after the race. "I didn't expect to win this way. It's really great to win this great race in Belgium."
"We have a good team here with many riders stronger this year than before. That helps a lot. It's great to win this race and finish second too."
"It's a really tough race but its really fun to win it."
It was a compact start to the race, with the peloton staying together through the early kilometres. Natalie van Gogh (Parkhotel Valkenburg) was the only rider to try some early aggression, the lone leader on the road with a maximum gap of one minute on an attentive peloton.
With van Gogh recaptured, the riders turned into the infamous 'hellingen' of the Flemish region, made treacherously slippery by rain during the race.
The rain may have played a part in a nasty crash with 60km remaining, a chain reaction taking down almost half the field and splintering the race. The worst off looked to be Chloe Hosking (Ale Cippolini) who was clearly in distress after being one of the first taken down in the massive pile-up.
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Hosking later tweeted that the worst of her injuries were bruises and she'd be prepared to race at the Commonwealth Games in just over a week's time.
The peloton was splintered by the crash and split up further over the Muur van Gerardsbergen but then reformed as the pace was slowed to allow dropped riders the chance to rejoin.
Elena Cecchini (Canyon-SRAM) and Amalie Didreksen (Boels-Dolmans) were the main players in trying to force the issue off the front as the peloton seemed content to merely to wait for the major climbs to split the race.
The group rode at tempo until the foot of the Krusiberg, where a major acceleration at the front from Cecchini saw the selection of some of the best riders over the top.
Van der Breggen used that acceleration and a bit of hesitation from the rest of the group to launch her attack off the front of the group.
The Olympic champion immediately established a gap, which ballooned out rapidly as the group of six behind slowed to rejoin with the chasing peloton.
The gap blew out to a full minute's advantage within the space of a few kilometres as the teams behind couldn't get organised and motivated to chase quickly.
Van der Breggen continued to power on as the pursuit finally picked up behind, initially losing a few seconds to the larger group but recouping the losses when the cobbled roads led uphill.
Ashleigh Moolman-Pasio (Canyon-SRAM) tried the most of anyone to escape the bunch, launching attack after attack, but couldn't come close to bridging the advantage to the runaway Dutchwoman.
A chasing group of four formed after the notorious pair of arduous climbs; the Oude Kwaremont and the Paterberg, with Moolman-Pasio, Amy Pieters, Annemiek van Vleuten and Kasia Niewiadoma attempting to stay clear of the third group on the road.
The second group was swallowed up by the chasers and it came down to a sprint for second place on the podium as Boels-Dolmans finished with a coveted 1-2 result in arguably the biggest race on the Women's World Tour calendar.