Denmark's Kasper Asgreen finished second for the Deceuninck-Quick Step team, whose best hope, favourite Zdenek Stybar, cracked with 27 kms left.
Norway's Alexander Kristoff took third place.
After showing good form in the GP E3 earlier this month, Bettiol, 25, became the first Italian to win the 'Ronde' since Alessandro Ballan in 2007.
Defending champion Niki Terpstra abandoned the race when he crashed 157 kms from the line.
The Dutchman suffered concussion and lost consciousness before being taken to hospital.
His Team Direct-Energie doctor said Terpstra was 'fine' but added that he would not be able to race in next Sunday's Paris-Roubaix, a race he won in 2014.
The Tour of Flanders is the second of five 'Monument' classics in the season, after Milan-San Remo and before Paris-Roubaix, Liege-Bastogne-Liege and the Tour of Lombardy.
(Reporting by Julien Pretot; Editing by Clare Fallon)
