The budget carrier will operate twice-weekly Manchester-Genoa flights, starting in April.
Genoa is a major cruising port, with several large lines offering departures.
Ryanair director of commercial Jason McGuinness said: “We are pleased to add this new route to Genoa as part of the UK’s summer 2022 schedule, offering our customers yet another amazing European destination to choose from when planning their long-awaited summer holidays."
Sale fares lead in from £19.99pp.
Ryanair has also announced a new route from Birmingham to Knock in Ireland, operating twice-weekly from March 2022.