Omega Pharma-Quick Step's Boonen, who won World Tour races E3 Prijs and Gent-Wevelgem on home soil last month, beat Filippo Pozzato (Farnese Vini-Selle Italia) and Alessandro Ballan (BMC) in a sprint finish at the end of one of the monuments of the European professional calendar.
Boonen, who won Flanders in 2005 and 2006, jumped off Ballan's wheel with 350m to go and held off Pozzato by a bike's length.
The trio had gone clear on the third and final climb of the Oude Kwaremont, the penultimate of 16 'hellingen' on a revamped 256km route.
"I was surprised as well as pleased to win, because I was not feeling at all good earlier on," Boonen said.
"I was feeling so rough that in fact I knew I couldn't drop the other two before the finish and I'd have to gamble on a sprint."
"Fortunately if I was tired, so were the rest. It's been an amazing race with an amazing result."
Many had labelled the race as a showdown between the Belgian and Fabian Cancellara but Radioshack-Nissan's Swiss star, who took the honours in 2010, crashed in the feed zone with 60km to go with a triple fracture of the right collarbone diagnosed.
A 15-man escape group featuring Anders Lund, Gert Dockx, Manuel Belletti, Peio Bilbao, David Boucher, Vladimir Isajtsjev, Massimo Graziato, Pablo Lastras, Maarten Tjallingii, Tyler Farrar, Sven Vandousselaere, Baptiste Planckaert, Tom Veelers, Daniel Schorn and Andreas Schillinger went away early and held a 3:20 lead when they came back into the finishing town of Oudenaarde for the first time with 95km to go.
Three distinct finishing loops, featuring 10 climbs including the Oude Kwaremont-Paterberg on three occasions, were to follow and after Cancellara left the race in an ambulance, another tip for the title, Sebastian Langeveld crashed out.
The GreenEdge man veered off the road to avoid some of the street furniture and hit a spectator as the pace in the peloton ramped up ahead of the run-in for the second ascent of the Oude Kwaremont where the last of the escape group was caught.
Sep Vanmarcke (Garmin-Barracuda) set the pace up the Oude Kwaremont with Ballan, Boonen and Pozzato in his wheel and that saw the lead group whittled down before Johan van Summeren crashed into the barriers on the Paterberg, holding up a host of riders and allowing an elite group of 11 to form.
But Boonen and team-mates Niki Terpstra and Sylvain Chavanel (Omega Pharma-Quick Step), Ballan, Vanmarcke, Peter Sagan (Liquigas-Cannondale), Juan Antonio Flecha (Sky), Matteo Tosatto (Saxo Bank), Luca Paolini (Katrusha), Vincent Jerome (Europcar) and Jacopo Guarnieri (Astana) failed to form a cohesive group and Team Sky pulled back a host of riders, including their team captain Edvald Boasson Hagen, back into the bunch before the final climbs of the Oude Kwaremont and Paterberg.
2007 Flanders winner Ballan instigated the attack on the 2.2km cobbled climb with fellow Italian Pozzato and Boonen following.
"Tommeke" just about managed to keep contact with the duo on the 350m ascent of Paterberg, which has an average gradient of 12.5%, while Paolini and Sagan failed in solo attempts to bridge the gap on the 13km run-in to the finish.
Boonen, with six Tour de France sprint stage victories, was always going to be the favourite in a sprint finish and so it proved with the 31-year-old now hoping to carry his Indian summer on and claim a fourth Paris-Roubaix title.
Boonen, a triple Paris-Roubaix winner, was cautious when asked whether he could equal compatriot Roger De Vlaeminck's record four victories in 'the Hell of the North' next Sunday.
"I've been racing all out for some time now and for now I just want to enjoy the feeling of taking three Flanders," Boonen said. "But I'll look forward to the challenge."
"Hopefully he'll be a bit tired," added Pozzato, "Otherwise we won't have that much of a chance against him."