Construction will begin in the second half of the year in the new First Street North development.
The 208-room, four star hotel will overlook a cultural centre with two theatres, five movie theatres, art galleries, restaurants and a new venue for outdoor performances.
Event capacities are yet to be confirmed, but there will be a public square equipped to host a variety of outdoor events and performances, together with a partially-covered arcade connecting through to Whitworth Street West and Oxford Road Station.
Meliá chairman and founder Gabriel Escarrer said: "The new cultural outlook for Manchester is an ideal framework for the growth of Innside by Meliá, a brand which originated in Germany and which enjoys a fantastic reputation amongst our customers and which we aim to bring to new cities in Europe."
C&IT this month revealed that ME London, which opens in June, will be occupied by BMW during the Olympic Games.