Nuyens narrowly outpowered Frenchman Sylvain Chavanel, with Switzerland's Cancellara forced to settle for third.
After 18 steep, short climbs, the trio took off three kilometers from the finish line from a group of around a dozen riders.
A former winner of the under-23 version of the Tour of Flanders but with none of cycling's top five 'Monument' Classics to his name until today, the 30-year-old Nuyens said joining the Saxo Bank team from Rabobank in the winter had made all the difference.
"I gained a lot of real confidence thanks to the team, the management, the riders — everybody," Nuyens told reporters.
"Signing for the squad was like a new start for me.
"I didn't feel good earlier in the day at all on any of the big climbs, but today was like playing a game of poker, all about calculation.
"And in fact my boss [Bjarne Riis] had told me in the morning before the race that if it came down to a sprint against Cancellara, I could win it." Cancellara, last year's winner, burst out of the pack with around 50 kilometers to go but suffered from cramp on the iconic Geraardsbergen climb and was pulled back to the bunch, before once again going clear with Nuyens and Chavanel in a dramatic finale.
"Even if you're superstrong like I felt, you're still beatable," Cancellara told reporters.
"In the last part of the race, though, I was so dead, I couldn't do more. I opened up the final sprint too early, but at the end I have to be happy with third."
