The move comes following the relaxation of travel restrictions by both UK and Tunisian governments.
With a fleet of 10 Airbus A320s, Nouvelair plans to operate two weekly services from the airport on Wednesdays and Sundays to Tunis from 29 March.
Karen Smart, managing director of Manchester airport, said the return of the carrier to Manchester is "terrific news" for the 100,000 passengers in its catchment area who travel to Tunisia each year.
Carl Denton, UK sales agent for Nouvelair, said: "After being restricted to a limited programme in 2021, we are very excited to restart operations again for 2022, with an expanded operation which will provide great access for holidays, business and most importantly to allow friends and families to reconnect with Tunisia again."
