The final Aer Lingus flight to Heathrow will leave Shannon on Sunday.
An average of 300,000 passengers a year travelled on the route but the new City Jet/Air France service to Paris begins on February 2.
The Shannon Airport Authority said there are no plans for any official ceremony to mark the last Aer Lingus flight to the London hub.
“It’s the end of an era and a sad day for many people but we’re firmly looking to the future now,” a spokesman said.
The twice-daily City Jet/Air France service to Charles de Gaulle will accommodate about 90,000 passengers per year with scope for further capacity.
It is expected the maximum wait for a transfer from the French capital to an onward destination in Europe, the US or Asia will be 12 hours.
The Shannon Airport Authority said Charles de Gaulle would provide connectivity to 248 non-stop destinations, compared with just 169 out of Heathrow.
The loss of the Heathrow service is another blow to the Mid-West hub. Compulsory stopovers for some transatlantic flights will be completely phased out by April under the Open Skies agreement.
Passenger numbers at Shannon reached 3.62 million in 2007, slightly down on the 2006 total of 3.63 million.
The airport saw double-digit passenger growth of 37 per cent and 10 per cent respectively in 2005 and 2006.
The unexpected Aer Lingus decision last August to axe the service caused outrage from the business community in the Mid-West. The privatised airline said switching its hub to Belfast was a commercial decision and irreversible.
The Atlantic Connectivity Alliance, formed by industrialists and local politicians in the region, vowed to continue its campaign to ensure the future viability of the airport.
CityJet, the Irish subsidiary of Air France, currently flies from Dublin to Paris Charles De Gaulle seven times a day.
It has also developed a broad network out of London City and flies business passengers to Dublin every day.
Based in Swords, Co Dublin, the carrier employs 720 staff and carried 1.6 million passengers last year.
The airline was recently awarded the prestigious ’Airline of the Year 2007/8’ bronze award by the European Regions Airline Association.