The Swiss powerhouse from Trek Factory Racing got the better of three Belgian riders at the conclusion of the 259km race, surging past BMC's Greg Van Avermaet to take the spoils in the 98th edition of the cobbled classic.
Belkin's Sep Vanmarcke completed the podium ahead of fourth-place Stijn Vandenbergh of Omega Pharma-Quick Step.
Cancellara joins Italian Fiorenzo Magni (1949, 1950, 1951) and Belgians Achiel Buysse (1940, 1941, 1943), Eric Leman (1970, 1972, 1973), Johan Museeuw (1993, 1995, 1998) and Tom Boonen (2005, 2006, 2012) as a three-times winner of the Ronde van Vlaanderen.
Boonen's Omega Pharma-Quick Step team looked to have a firm grasp on matters as the race entered its decisive final third - but Cancellara kept his cool before launching a pulsating attack on the penultimate climb of the day, the Oude-Kwaremont.
Cancellara was joined by Vanmarcke in pursuit of leaders Vandenbergh and Van Avermaet. The quartet came together after the final climb of the Paterberg, 13km from the finish.
Both Vandenberg and Van Avermaet attempted to break away in the long, flat drag into Oudenaarde before the finale took on something of a track veneer as the four leaders came to a near standstill inside the closing kilometre.
Thirty-three-year-old Cancellara surged from the back and had too much power for a Van Avermaet exhausted after a typically aggressive ride on home soil.
Milan-San Remo winner Alexander Kristoff (Katusha) crossed the line 20 seconds later for fourth place ahead of OPQS pair Niki Terpstra and Boonen. Britain's Geraint Thomas (Sky) recovered from an early crash to take eighth place ahead of Bjorn Leukemans (Wanty) and Sebastian Langeveld (Garmin-Sharp).
The race started under light drizzle in Bruges and was marred by a succession of early crashes which saw the likes of Flanders debutant Luke Durbridge (Orica-GreenEdge) and Johan Vansummeren (Garmin-Sharp) taken to hospital after serious incidents.
Belgium's Vansummeren, the 2012 Paris-Roubaix champion, collided with a spectator at high speed on a central reservation in the middle of a road. The elderly lady was reported to be in a critical condition in hospital.
Two-time champion Stijn Devolder (Trek Factory Racing) was also involved in two heavy spills in a frantic race littered with incident. Vanmarcke, runner-up to Cancellara in last year's Paris-Roubaix, crashed earlier on in the race, while Ukrainian veteran Yaroslav Popovyvh (Trek Factory Racing) crashed into a gutter after his handlebars appeared to catch on the coat of a spectator on the side of the road.
The series of crashes that held up large swathes of the peloton brought about the isolation of Slovakian pre-race favourite Peter Sagan. Still in search of his maiden win in one of cycling's five Monuments, Sagan struggled to make an impact without his Cannondale team-mates and finished outside the top ten after the streamlined pack of favourites splintered on the final two of 17 climbs.
With OPQS team-mates Boonen, Terpstra and Zdenek Stybar in the main chasing group, Vandenberg refused to help compatriot Van Avermaet after the two broke clear with 30km remaining.
Van Avermaet's move came after BMC team-mate Taylor Phinney had been part of the race's major break, a 10-man group which formed after 40km of racing. Making his debut in the race, American Phinney was the driving force as the break built up a maximum advantage of just over six minutes.
South African Daryl Impey (Orica-GreenEdge) was the last man standing for the break. Impey was caught on the Steenbeekdries climb 40km from the finish at a time when OPQS seemed to have a firm grip over the race.
Vandenbergh rode up the road with Edvald Boasson Hagen (Sky) and Dries Devenyns (Giant-Shimano), while both Boonen and Terpstra controlled matters with the main pack.
The race came back together with 32km remaining before Van Avermaet and Vandenbergh broke clear on a sweeping descent ahead of the Kruisberg climb. Both Sagan and Vanmarcke rolled the dice on the short and sharp climb in pursuit of the leaders, who held a slender 20-second lead.
The scene was perfectly set for Cancellara to make his move on the third and final ascent of the legendary Oude-Kwaremont, 18km from the finish. Just as the chasing group was joined by the remnants of the peloton, the Swiss combined with Vanmarcke to power clear.
Sagan briefly led the chase but it was to no avail. Once Cancellara and Vanmarcke had joined forced with Van Avermaet and Vandenberg on the front of the race over the top of the Paterberg there was little doubt that the leaders would stay ahead all the way to the finish.
Cancellara will have the chance to enter the history books next Sunday as the first rider to secure a third Flanders-Roubaix double. Given his form, few would bet against the man they call 'Spartacus'.
- Sports & Recreation
- Greg Van Avermaet
- Tom Boonen
- Stijn Vandenbergh
- Trek Factory Racing
- Sep Vanmarcke