The film by US director Sean Baker beat the 21 other films in the competition lineup, including entries by established directors like Francis Ford Coppola and David Cronenberg.
Jury members including US actor Lily Gladstone and Japanese director Hirokazu Kore-Eda have said they are well aware their decision could make or break a director’s career.
As head of the jury, Barbie director Greta Gerwig praised Anora as an “incredible, human and humane film that captured our hearts”.
Baker’s win has made him one of the leading voices of American indie cinema. He dedicated the film to all sex workers.
“This literally has been my singular goal for the past 30 years, so I’m not really sure what I’m going to do with the rest of my life,” he said, while also thanking the film’s star, Mikey Madison, as well as his wife and producer.
Madison plays the character of the title, who meets Vanya, the immature son of a Russian oligarch with seemingly unlimited money, while working at a strip club.
Vanya, played by Mark Eydelshteyn, hires Anora to be his girlfriend for a week, deciding on a whim to take his private plane to party in Las Vegas, where they get married.
That decision upsets his disapproving parents so much that they jet over from Russia to ensure he gets an annulment.
The second-place Grand Prix went to All We Imagine as Light, the first Indian entry in 30 years.
It wowed critics with its poetic monsoon-set portrayal of two women who have migrated to Mumbai to work as nurses.
Emilia Perez also won the third-place Jury Prize for its French director, Jacques Audiard.
And a devastating Iranian film about a family torn apart by the country’s recent women-led protests, The Seed of the Sacred Fig was given a special jury prize for “drawing attention to unsustainable injustice”.
Its director Mohammad Rasoulof, 51, fled Iran to avoid a lengthy prison sentence just before the festival.
Rasoulof said his heart was with the film’s crew, “still under the pressure of the secret services back in Iran”.
“I am also very sad, deeply sad, to see the disaster experienced by my people every day … the Iranian people live under a totalitarian regime,” he said.
The 77th edition of the festival on the French Riviera, which began on May 14, saw several highly charged feminist and political movies.
A trans woman won best actress for the first time, as Karla Sofia Gascon took the award for the audacious musical Emilia Perez, in which she plays a Mexican narco boss who has a sex change.
The jury shared it between Gascon and her co-stars Zoe Saldana and Selena Gomez – saying they were rewarding the “harmony of sisterhood” – though only Gascon was at the ceremony.
She dedicated it to “all the trans people who are suffering”.
“We all have the opportunity to change for the better, to be better people,” she said.
“If you have made us suffer, it is time for you also to change.”
Meanwhile, there were fewer meaty roles for men this year.
But Jesse Plemons took the prize for Yorgos Lanthimos’s bizarro series of short stories, Kinds of Kindness, though he was not present to accept it.