The low-cost carrier will operate two services each week to Alicante and Palma, commencing on 1 June.
The news comes two years since a deal was struck to bring the airport back into public ownership.
It has since undergone investment to its terminal building, including a “£1 million overhaul” to its security area and redevelopment of its arrivals hall.
Tees Valley mayor Ben Houchen called Ryanair’s arrival “a seismic day” for the airport.
“Securing a low-cost airline was always the crucial part in our rescue plan for Teesside and, less than two years after agreeing a deal to buy back our airport, we have made it happen,” he said.
“I want to thank our excellent team who have had a hard year but have got this over the line, making sure Ryanair understands and appreciate the potential Teesside has.”
