Cereal farmer Paul Francois has been fighting Monsanto, a formerly US company which was bought by Germany's Bayer last year, for the past 12 years.
In the first ruling of its kind against Monsanto anywhere in the world, a French court in 2012 found it guilty of poisoning Francois.
He said he began experiencing symptoms including blackouts, headaches and loss of balance and memory after inhaling fumes while using the now-banned weedkiller Lasso.
Monsanto appealed and lost in 2015 but decided to go a third round.
"I won, and I'm happy, but at what cost?" Francois told reporters after the verdict.
He denounced what he called years of "legal harassment" by Monsanto, which can still appeal Thursday's ruling by the Cour de Cassation, a top French appeals court.
The ruling, he said, was "a message to the government," which he urged to ban other toxic pesticides that contain glyphosate, used in Monsanto's top-selling Roundup.
"History will judge them for not acting," he said, referring to a campaign pledge by President Emmanuel Macron to phase out glyphosate in France, which he backed down on last year.
Monsanto is facing thousands of US lawsuits over glyphosate exposure, and last month was ordered by a San Francisco court to pay around $80 million to a retiree suffering from non-Hodgkin's lymphoma.
'Not a chemist'
Francois said he fell ill in 2004 after accidently inhaling fumes from a vat containing Lasso, a monochlorobenzene-based weedkiller that was legal in France until 2007 but which had already been banned in 1985 in Canada and in 1992 in Belgium and Britain.
He argued that Monsanto was aware of Lasso's dangers long before it was withdrawn from the French market, and sought damages of more than one million euros for chronic neurological damage that required long hospital stays.
The court in Lyon, southeastern France, rejected the company's appeal but did not rule on how much Monsanto might have to pay, which will be determined in a separate ruling.
It did order the company to pay 50,000 euros immediately for Francois's legal fees.
In its ruling, the court found that Monsanto should have clearly indicated on Lasso's labelling and instructions for use "a notice on the specific dangers of using the product in vats and reservoirs".
"The plaintiff's assumed technical knowledge does not excuse the lack of information on the product and its harmful effects -- a farmer is not a chemist," it added.
Speaking after the verdict, a lawyer for Monsanto France, Jean-Daniel Bretzner, said it would probably appeal, since the ruling applied to Lasso's producer -- in this case, Monsanto Europe.
Parent company Bayer confirmed it was weighing an appeal.
"Supposing that Paul Francois was accidently exposed to Lasso, by definition such exposure is rare," it said in a statement.
Wave of lawsuits
It was the latest conviction against Monsanto involving its weedkillers and pesticides, which have been widely used around the world for years.
Last month, a San Francisco court ordered the $80 million pay-out to a retiree who blames its popular Roundup weedkiller, which contains glyphosate, for causing his non-Hodgkin's lymphoma.
The company said it would appeal as it faces thousands of similar lawsuits in the United States.
It had already been ordered last year to pay $78.5 million to a California groundskeeper who attributed his non-Hodgkin's lymphoma to using Roundup as well as Monsanto's Ranger Pro.
Monsanto denies that Roundup causes cancer and has challenged findings by the International Agency for Research on Cancer, an arm of the World Health Organization (WHO), which classified glyphosate as a "probable carcinogen" in 2015.
But Bayer, which paid $63 billion for Monsanto last year, has seen its stock plunge some 40 percent since the takeover was completed last June, largely reflecting fears of Monsanto's exposure to lawsuits.