Ryanair cancelled 75 flights on Thursday as French air traffic controllers (ATC) went on strike, the airline said.
The disruption for flights due to operate in French air space is set to continue with further strikes planned on Friday, Saturday and Sunday.
Thousands of football fans from the UK are due to travel across the Channel in the coming days to support England, Wales or Northern Ireland at the Euro 2016 football tournament.
It is the 50th French ATC strike since 2009 and the ninth in the past 10 weeks, according to Ryanair.
The budget airline's chief marketing officer, Kenny Jacobs, said: "This latest strike action by the French ATC unions is a clear escalation of their attempts to cause as much disruption as possible, and not only will European consumers heading off in huge numbers on their summer holidays be affected, football fans from all over the continent face massive disruption as they get ready for the European Championships, which begin next week.
"It is also important to note that the tourism sectors in Italy and Spain are continuing to be hit hard by these strikes, with thousands of flights to both destinations cancelled in the past few weeks alone, meaning hotel beds lie empty and restaurants remain half-full due to tourists being unable to fly over France to get there."
Ryanair is urging people to sign a petition calling on the European Commission to introduce measures to alleviate the impact of French ATC strikes, such as requiring the unions to engage in arbitration to resolve their claims and requiring that flights over France are protected.