Socialist Prime Minister Manuel Valls hailed the ruling following years of legal battles and sometimes violent protests over the plan, saying it "proves once more that the project is perfectly legal and complies with current regulations."
But an umbrella grouping of activists vowed that they would "not allow any work or evictions to begin" for the Notre-Dame-des-Landes airport, which will be a second facility serving the western city of Nantes.
Yannick Jadot, a former Greenpeace activist who is the green party EELV's candidate in France's presidential elections next year, slammed the ruling, calling the project "absurd and destructive".
It was approved in 1970, but mothballed because of the oil crisis.
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Since Socialist prime minister Lionel Jospin revived the plan in 2000, it has been the subject of heated public debate and dozens of legal challenges.
Dairy farmers resisted eviction, while environmentalists said the project threatened important wetland supporting dozens of protected species of birds as well as newts and voles.
There have been several violent standoffs as riot police tried to dislodge the squatters, some of them living in treehouses.
In 2012 then prime minister and current Foreign Minister Jean-Marc Ayrault -- who hails from Nantes -- set up a "dialogue committee" that found in favour of the project while strengthening environmental safeguards.
Then in June this year, voters in the Loire-Atlantique region approved the project in a referendum, the "Yes" vote winning with 55 per cent.
"The people have voted, justice has ruled: work begins now!" Philippe Grosvalet, the region's Socialist president, said in a statement.
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