The 25-year-old Giant-Shimano rider won the nine-man group sprint 20 seconds behind solo winner Niki Terpstra (Omega Pharma-QuickStep). He led home a high class group of favourites including Sep Vanmarcke (Belkin), Peter Sagan (Cannondale), Tom Boonen (Omega Pharma-QuickStep) and Geraint Thomas and Bradley Wiggins (both Team Sky).
"Today was a situation where QuickStep had a big advantage to have three guys in the front group," said Degenkolb to the press after the race. "I really don't regret anything I did in the race and right now I'm just satisfied and happy with my second place."
"To be honest, when I saw the stone given to Terpstra, of course that was a little disappointing but I can be very, very satisfied with my result and I'm just happy," said the rider who finished 19th on his debut in Roubaix in 2011.
"I love this monument, I love Milano-San Remo and I love Flanders. It has been a big dream of myself to win one of these big Classics and I was close today," said Degenkolb clearly drawing confidence from the result.
Degenkolb, heaped praise on his teammate Bert de Backer, who joined a dangerous attack instigated by Tom Boonen with collusion from Geraint Thomas about 60km from the finish. De Backer's infiltration meant Degenkolb could save his own legs for the final sprint, in which he edged out Cancellara, who took third.
"I'm also very thankful to my team, and I think we did a really good, really smart race by sending Bert De Backer in the breakaway and until the velodrome he was leading the group trying to bring Terpstra back. I could do a good sprint because of him."
Degenkolb's podium finish caps a successful early season for the German rider. He won Gent-Wevelgem two weeks ago and won the opening stage of Paris-Nice and the stages race's jersey competition.
Comparing victory in 200km Gent-Wevelgem with second in the so-called Queen of the Classics, Degenkolb said, "A win is always nice but you have to see the difference between Paris-Roubaix and Gent-Wevelgem. This is one of the toughest races - maybe the toughest - but yeah it's a really awesome result and I'm smiling inside right now and enjoying the moment."
Second today betters Degenkolbs previous best result in a monument - fifth in Milan-San Remo in 2012.