The Italian Deceuninck-Quick-Step rider proved far too strong for the rest of the peloton in the bunch finish at the end of the 200.5km run from Ghent to Ninove.
Jake Stewart (Groupama-FDJ) trailed in second, Sep Vanmarcke (Israel Start-up Nation) finished third and Heinrich Haussler (Bahrain Victorious) took fourth.
The 26-year-old Ballerini won the first two stages of the Tour de la Provence earlier this month, but the victory in a WorldTour race was the biggest of his career.
“It’s a dream come true,” Ballerini said post-race.
“This is the start of the really big classics. I love it and I love this team. It was my dream since I was a baby when I saw my first race on TV.”
Earlier, South Africa’s Ryan Gibbons (UAE Team Emirates) was part of a five-man breakaway that was reeled in with 40km to go.
The national road champion eventually finished in 136th place, 9:15 behind the winner.
Meanwhile, the women’s Omloop Het Nieuwsblad over 124.4km was won by Dutch star Anna van der Breggen who triumphed by 23 seconds after breaking clear in the closing stages.