The BMC rider prevailed in a sprint at the end of the 200.3 kilometre race that concluded with five laps of a 16km circuit.
The 22-year-old from Sheffield peeled off the wheel of team-mate Michael Schaer, who led around 35 riders over a cobblestone section inside the final km, before making his burst for the line.
Blythe beat Cofidis rider Adrien Petit into second with John Degenkolb, winner of five stages at the Vuelta a Espana, only third.
Blythe said. "I attacked with about 700 meters to go, which was a bit risky, but I gave everything to hold it to the line."
Blythe has been in fine form recently and racked up four top five finishes from sprints in September, including a second place on Sunday on the final stage of Circuit Franco-Belge.
It was his second win of the year, following on from a success at Paris-Correze in August.
"It's a bit late, but I've finally got some good form now," he said. "It's nice to win at the end of the season like this," he added.
Former Tour de France winner Andy Schleck was back in competition, after four months out with a fractured pelvis, but did not complete the race.
The race is also known as the Memorial Frank Vandenbroucke after the late Belgian rider who won the event in 1996.