Employees in Germany, Sweden, Ireland, Belgium and the Netherlands are taking part in the one-day walkout, the largest in the history of Ryanair.
The Irish airline has announced the cancellations in recent days of 250 flights in and out of Germany, 104 to and from Belgium and another 42 in Sweden and its home market of Ireland.
Some 42,000 travelers are expected to be affected by the strike in Germany alone, with the majority of passengers switched to another Ryanair flight and the remainder either refunded or rerouted, Presstv reported.
Europe's largest low-cost carrier averted widespread strikes before Christmas by agreeing to recognize unions for the first time in its 30-year history.
Protests, however, continued over slow progress in negotiating collective labor agreements.
"What I find unjustified is that the pilots draw the short straw, because people want to fly cheaply," said Daniel Flamman, one of several passengers at Frankfurt airport who said they sympathized with the pilots.
"It's annoying that it's happening in the summer holidays, but it's the only means they have."
Ingolf Schumacher, pay negotiator at Germany's Vereinigung Cockpit (VC) union, said pilots had to be prepared for "a very long battle" and that it could take months to push through change at the airline.
Michael O'Leary, Ryanair’s chief executive, was once quoted as saying he would rather cut off his hand than recognize unions and on another occasion crossed a picket line of baggage handlers to help load a plane.
Last month, Ryanair cancelled 300 flights when cabin crews in Belgium, Portugal and Spain went on strike for 48 hours.