Van Vleuten'ws move on the Paterberg was one of dogged determination as she clawed her way clear of an elite group on the steepest portion of the climb. She had a 10-second gap for most of the flat run to the line, holding off a working group of seven to win solo in style.
Grace Brown (Team BikeExchange) was one of the strongest riders in the race and had a strong sprint to finish third, behind Lisa Brennauer (Ceratizit-WNT) won took the second step on the podium.
"I had hoped for this for so long", said van Vleuten. "The Tour of Flanders has been marked in my agenda for years.
"I definitely wanted to make the turn up the Paterberg first. There were 13 more long kilometres, but luckily I was well guided from the car."
Van Vleuten broke new ground on her career, her move to new team Movistar proving a successful joint venture as the Spanish squad took its first Tour of Flanders win in its history.
"Movistar had never won a top classic. We will therefore celebrate that anyway", said Van Vleuten, who shrugged off talk of retirement. "Sometimes I get the question when I will stop, but with a new team I keep it nice to myself."
The peloton was mostly together after the initial run of climbs that brought the main bunch closer to the finish of the 152-kilometre race in Oudenaarde.
Van Vleuten was the first rider to ignite the action in the race, attacking hard up the Kanarieberg and seeing a number of riders shed out the back of a rapidly thinning peloton. After the ascent, there was a general regrouping and Audrey Cordon Ragot (Trek-Segafredo) used the opportunity to launch an attack.
Jumping from 42 kilometres from the finish, the French champion got out to a minute lead, but a solo rider was always going to struggle against the peloton and with some hard chasing by Sarah Roy (Team BikeExchange), she was caught just before the ascent of Oude Kwaremont with 16 kilometres to go.
The famous climb was the scene of a series of attacks that saw the best riders rise to the top with van Vleuten then Brown the first two over the peak of the climb.
Brown tried an attack on the flat after the Oude Kwaremont, but perhaps with memory of her similar move to take the win in the recent Brugge-De Panne, the group behind committed and brought her back with van Vleuten to the fore.
Van Vleuten then used all of her strength, nous and bloody-mindedness to claw her way up the steep slopes of the Paterberg, at one point grabbing at the barriers to propel her way up the climb. She crested the climb with 13 kilometres to go with a small advantage but stretched it out a bit to ten seconds on the flat.
A good chase behind kept the gap to van Vleuten pegged to that 10-second mark on the final flat kilometres on the run into the finish. That cooperation lasted into the final kilometres when a small attack from Longo Borghini disrupted the momentum of the chasers and van Vleuten doubled her lead to 20 seconds, a race-winning margin for the Dutch superstar.
Van Vleuten soloed in to take her second Tour of Flanders win, while the sprint behind for second saw Lisa Brennauer (Ceratizit-WMN) take the runner-up spot, with Brown in third.