Gilbert, 34, attacked alone with 55km of the 261km race to go and held on to win as world champion Peter Sagan and Olympic gold medallist Greg Van Avermaet crashed 17km from the end of the cobbled classic.
Van Avermaet, the in-form rider this spring, picked himself up to take second place ahead of Gilbert's Quick Step Floors teammate Niki Terpstra but the crash with Sagan and Oliver Naesen potentially robbed the race of a grandstand finish.
Instead, Gilbert's audacious solo breakaway paid dividends.
Victory in Flanders added to the 2012 world champion's impressive resume that includes stage wins at all three Grand Tours and victories in two other 'Monument' races – Liege-Bastogne-Liege and the Giro di Lombardia.
Gilbert has also won major one-day classics including Amstel Gold, Fleche Wallonne and Clasica de San Sebastian, but this victory tops the lot.
It was his seventh participation at Flanders and first for five years having previously come third in 2009 and 2010.
But while a BMC teammate of Belgian compatriot Van Avermaet's he was forced to ride the Ardennes classics rather than the cobbled ones.
