The carrier said it was stopping routes from Belfast airports, blaming the "refusal" of ministers to suspend or cut air passenger duty and a lack of "COVID recovery incentives" from the two hubs.
Ryanair has blamed a lack of support from the UK government and Belfast's two airports as it confirmed it was pulling out of Northern Ireland.
The Dublin-based carrier's routes from Belfast International Airport to a number of European destinations will cease on 30 October.
It will also stop a number of seasonal flights from the separate Belfast City Airport.
Ryanair had already stopped flying from the City of Derry airport earlier this year.
In a statement, it blamed the government's "refusal to suspend or reduce APD (air passenger duty) and the lack of
COVID recovery incentives from both Belfast airports".
Ryanair said aircraft "will be reallocated to lower cost airports elsewhere in the UK and Europe for the winter schedule which starts in November".
A spokesperson for Belfast International Airport: "It is disappointing that Ryanair has now decided to withdraw operations from the entire Northern Ireland market at the end of October, having variously had a presence in all three local airports in recent years.
"It has been a difficult period for aviation and a time when consumers need some stability and faith in the Northern Ireland air transport network."
The spokesperson said the move had been anticipated and that it had been "engaging with our existing and other new airlines to provide continuity on the routes to be vacated by Ryanair" and to help sustain local jobs.
"We hope to be able to make announcements regarding fresh route development in the near future," the spokesperson said.