In an unpredictable finish at the end of the 256km race from Oostkamp to Ninove, 12 riders still had a chance with two kilometres to go. Nuyens came out less than a tire-length ahead to grab the biggest victory of his career in a time of six hours and 42 seconds.
Nuyens was taken on by Saxo Bank after classics giant Cancellara left the team: The Swiss rider was lined up as virtually the only favourite for the second cycling "monument" of the season having coasted to victory in a smaller classic race midweek and by virtue of his unrivalled domination of Flanders and Paris-Roubaix last year.
But the 30-year-old Nuyens worked his way into the elite 12-man group at the foot of the final climb, the Bosberg, and only he and Chavanel could react when Cancellara attacked inside the final four kilometres of action. Despite another late burst from Cancellara, it was Nuyens who emerged to take a narrow but famous win in front of his home crowd.
Quickstep's Tom Boonen, winner of last week's Gent Wevelgem, came two seconds behind to take fourth, while Herzele-born Staf Scheirlinckx of Verandas Willems came eighth.
"This victory is unexpected, as I wasn't at my best today, but I raced intelligently," said Nuyens, who was competing in his seventh Tour of Flanders. "I felt very relaxed during the final sprint. It was only in the final 50 metres that I started to fully realise what was happening - that I was about to win this beautiful race."