The inaugural service to Dublin left at 08:00 BST and others will follow.Passenger flights stopped in 1993, although the airport has still been a base for private aircraft and flying schools and is also used by the military.
'Huge significance'In 2017, the airport was given £4.75m by Cumbria's Local Enterprise Partnership to upgrade its terminal and runway
Tourism bosses hope the flights will encourage thousands of people to travel to and from Cumbria.
Kate Willard, director of partnership development at the Stobart Group, said the relaunch was of "huge significance" for the Northern Powerhouse as it will connect regions and economies. But some people are unhappy about the effect on climate change and are staging a protest outside the airport. Helen Davison, a Green Party councillor for Carlisle City Council, said: "It is time we stop increasing the amount of available flights and it's also time the government properly taxed flying."Aviation fuel currently doesn't have a tax on it so it is unfairly subsidised against the other forms of greener travel."
Glyn Jones, chief executive of Stobart Aviation, said no-one was debating there was an environmental responsibility, and pointed out that Southend Airport generated a quarter of its own electricity.
Services will initially operate 28 flights a week to Belfast, Dublin and London Southend, with Loganair using 33-seater Saab 340 aircraft for the journeys.Jonathan Hinkles, managing director of Loganair, told BBC Cumbria: "There's plenty of potential for further routes, particularly to some of the further points within the UK."