The German Lotto Belisol rider beat Italians Danilo Napolitano (Acqua & Sapone) and Jacopo Guarnieri (Astana) into second and third respectively.
The official time was three hours 46 minutes and 13 seconds.
The podium at the end of the 170.7-kilometre ride from Lochristi to Knokke-Heist in the north-east of the country is reflected in the general classification after two of the race's five stages.
Second-placed Napolitano is eight seconds behind Greipel, with Guarnieri a further eight behind his compatriot.
"I am very happy with my sprint today," said Greipel after the race. "It's true what they say, only the strongest will succeed at Knokke-Heist.
"I was fully launched at 800m by Greg (Henderson) at the wheel of Jacopo Guernieri. I was able to play out a perfect sprint and I got out at the right time, even if it was more complicated than it seemed."
Friday's third stage is a 173.5km trek to Beveren.