The German Lotto-Belisol rider pipped Danilo Napolitano and Kenny van Hummel in an exciting sprint finish which left the crowd in raptures.
Napolitano appeared to peak too early and was caught at the finish with Greipel left to celebrate an inspired victory.
On the route from Mechelen to Buggenhout, the lead group remained together until the final intermediate sprint, 17 kilometres from the finish.
Greipel, who took what turned out to be a photo finish, was relieved as he celebrated the win.
"It was close, but a win is a win," Greipel said. "All I thought was that I had won.
“Today I was maybe not the strongest, but I had the strongest team.
"But I was strong enough. I was ill for four days last week and I still miss some power, but the shape is good. In the morning ride we will just try again. "