Second behind the Saxo Bank rider, one minute 15 seconds back, was favorite Tom Boonen of Belgium with compatriot Philippe Gilbert in third at two minutes 11 seconds.
A year after being forced to abandon the race when his chain broke on the Koppenberg climb, Cancellara looked in trouble again when he had to change his bike twice.
But the Olympic and world time trial champion's luck then turned when he forged ahead with Boonen on the 10th of 15 climbs, 42 kilometers from the finish.
The 29-year-old finally shed the Belgian national champion on the Geraardsbergen, Flanders' most iconic ascent, for the third major Classic win of his career.
"Fortune's wheel finally went my way in this race," Cancellara told reporters. "But it was only in the last three kilometers I really felt I could enjoy this.
"I stayed calm when I had the mechanical problems and kept cool when I went away with Boonen. But none of this was planned, neither the first attack or the second.
"Finally I got the win, though it was very complicated from beginning to end." Moments before he secured Switzerland's first win in Flanders in 87 years, Cancellara waved a tiny gold angel to the television cameras.
"My wife gave it to me before the race, she wanted me to take something from home when I went away," he explained.
"I didn't want to at first, with all the race food there's not much space. But it's nice to do something that shows you remember your family when you're away from home." The winner in 2005 and 2006, Boonen explained what had gone wrong this time round.
"I got cramp in one leg and my back wheel slipped at exactly the wrong moment," he said.
"It was only a small crisis but by the time I got over it, it was too late." Back in Flanders for the first time since 2005 when he finished 28th, American Lance Armstrong came 27th, two minutes 35 seconds down on Cancellara.
"It went better than expected even though I felt a little like a fish out of water at times," the seven-times Tour de France champion told Belgian television.
"I stayed consistent throughout the race, didn't panic.
(Overall), the trend is good."
