Scottish airline Loganair will connect the Carlisle Lake District Airport airport, owned and operated by the Stobart Group, with London Southend, Belfast City and Dublin.
The first flight, to Dublin Airport, was due to take off on Thursday morning following a blessing from the Archdeacon of Carlisle, the Ven Lee Townend.
Kate Willard, director of partnership development at the Stobart Group, said: "It's going to be an extraordinary day for the airport and for the city of Carlisle."
She said the launch was of "huge significance" for the Northern Powerhouse as it would connect regions and economies.
Ms Willard added: "Airports are symbols of confidence and this shows Cumbria is open for business."
She said the airport would bring new tourists to attractions in the Lake District, as well as making travel easier for Cumbrian residents.
The carrier was initially due to resume flights in June last year but this was delayed due to a shortage of air traffic control staff.
Ms Willard said: "It was unbelievably disappointing for everybody, particularly for the team who worked so hard.
"We have moved forward and we have a full cohort of air traffic control staff here ready."
Loganair will use 33-seater Saab 340B aircraft to operate the flights, with nine return services on weekdays and five at weekends.
The site is a former RAF airfield and its last commercial passenger flight was in 1993.