The budget carrier will base two aircraft in the north-east, allowing it to grow its Newcastle route network to 19.
New additions include Chania, Fuerteventura, Gran Canaria, Ibiza, Krakow, Menorca, Milan, Paphos, Riga and Zadar.
In total, Ryanair says it will operate more than 130 flights a week from Newcastle during the summer peak, 40 more than it did in summer 2019.
It added the move represented an investment amount to around £150 million, one that would create 60 direct new jobs.
Ryanair director of marketing Dara Brady said: "The opening of this base and introduction of these new routes from Newcastle reinforces our commitment to increasing connectivity, travel options and inbound tourism to the area, as Ryanair will now offer 40% more capacity than it did pre-pandemic."
Newcastle airport chief executive Nick Jones added: "Today sees a significant investment and commitment from Ryanair at Newcastle International airport which will also benefit the wider north-east, creating hundreds of new jobs and providing an even bigger choice of destinations.
"From today, Ryanair will operate a total of 19 routes from our airport, including the brand new destinations of Zadar in Croatia, Chania in Crete, Milan in Italy and Riga in Latvia. We look forward to welcoming even more Ryanair passengers through our doors this summer."
