Deneuve's defence came after the reclusive French film legend Brigitte Bardot castigated attacks on a man who is arguably France's leading actor with roles in nearly 170 films.
The hulking 64-year-old star's move to Belgium has been derided as "pathetic" by Prime Minister Jean-Marc Ayrault while another top French actor, Philippe Torreton, publicly accused him of sulking like a playground creep.
Deneuve, a chiselled blonde actress whose career spans nearly a half-century, questioned Torreton's credentials to attack a giant of French cinema in an open letter in the left-wing Liberation daily .
She told Torreton her "anger was borne of your hasty judgements made without thinking and this pettiness," adding: "You take aim at his physique! At his talent!
"'This mess' that you speak of. What right, what democratic motive do you claim as your dirty condemnation?" she said. "The actor is a giant and you are expressing nothing but your bitterness.
"I shudder to think what you would have done in 1789," she said, referring to the French Revolution in which the king and queen were beheaded and tens of thousands – notably aristocrats and the bourgeois – were killed.
Deneuve also flayed the prime minister's "pathetic" remark and a comment by Labour Minister Michel Sapin that the shift to Belgium signified Depardieu's "personal decline" as "words not worthy of men of state."
Torreton had in a vitriolic attack on Tuesday accused Depardieu of being an outspoken, money-obsessed lout with "dictator friends."
The latter was a reference to Uzbekistan's strongman leader Islam Karimov whose pop star daughter recently recorded a duet with Depardieu.
Bardot – who keeps out of the public eye and only speaks on animal issues – had also defended Depardieu, who she said had been "the victim of extremely unfair persecution".
She told Torreton to "keep his venom, his vulgarity, his mediocrity and his jealousy to insult someone worthy of the bother".
Depardieu on Sunday threatened to give up his French passport and take up Belgian citizenship to protest at the Socialist government's new tax hike on the rich.
He made the threat after Ayrault called him "pathetic" for making Belgium his formal place of residence, a move designed to help the actor avoid the French tax.
Depardieu has joined some of France's wealthiest business figures in Belgium following moves by President Francois Hollande's government to tax annual incomes above one million euros ($1.3 million) at 75 percent.
Unlike France, Belgium does not impose a wealth tax and has not had one since 1830. Its income and inheritance taxes are also lower.
In his letter, Depardieu, who has extensive business interests including wine estates and three Paris restaurants, accused the Socialists of driving France's most talented figures out of the country.
He said that over 45 years of working and running businesses in France he had paid €145 million into state coffers. He claimed to have paid 85 percent tax on his earnings in 2012.