She beat Nathalie Portman to the punch, who was widely tipped to win for her intense turn as Jackie Kennedy in ‘Jackie’.
‘Elle’ also captured best foreign language film over the heavily favored German-Austrian dramedy "Toni Erdmann."
The stateside victory came after the project from Dutch director Paul Verhoeven -- of 'Basic Instinct' and 'Total Recall' fame -- was rejected by a number of American actresses who found the role to be too controversial.
The director ultimately found his lead in Huppert, the veteran French actress who beat out Natalie Portman, Ruth Negga, Amy Adams and Jessica Chastain to take home her first prize at the Globes ceremony, a prelude to the Oscars.
In the psychological thriller, Huppert plays a powerful businesswoman who, after being brutally assaulted, tracks down her attacker in pursuit of revenge.
As he accepted his award, Verhoeven said he was "amazed" to win because "the movie is a bit controversial and people have been angry."
In his speech, he also paid warm tribute to Huppert: "It was wonderful to work with you -- you are wonderful. I love you, I love you, I love you."
A shocked Huppert noted the diversity in the room as she accepted her prize.
"There are people from all over the world in this room -- from China to America to Europe," she said. "Do not expect cinema to set up walls and borders."
Huppert will now have momentum behind a bid for a best actress nomination for next month's Oscars. The Academy of Motion Picture Arts and Sciences will announce those nominations on January 24.
The 63-year-old actress, who has worked with some of the world's greatest directors, told French news agency AFP in an interview prior to the Globes that her character's twisted relationship with her rapist adds a rich dimension to the role.
"It has been rightly said that she does not behave like a victim. She has an enormous number of responsibilities," said Huppert, who said she was interested in the role after reading the novel by Philippe Djian on which the film is based.
She called her character "somewhat of a loner, fairly courageous -- who the people around her depend on -- and who has a kind of generosity."
Billed as the biggest event in the showbiz calendar, the Hollywood Foreign Press Association's annual awards ceremony is a draw for filmmakers and actors looking to create some buzz ahead of February's Academy Awards.
French director Houda Benyamina, whose first feature film, ‘Divines’ was also competiting for best foreign language film, failed to pick up an award.
Benyamina’s film, which scooped the coveted Caméra d’Or (Golden Camera) award at the Cannes Film Festival last year, was up against "Elle" and the other French contender "The Salesman".
‘La La Land wins’
The big winner was the modern-day musical "La La Land" which pirouetted its way into major Oscars contention Sunday as it swept the board at the Globes.
Damien Chazelle's nostalgic tribute to the Golden Age of Hollywood musicals picked up all seven of the statuettes for which it was nominated -- giving the film momentum as it launches its campaign for next month's Academy Awards.
Trump On Stage
The US presidential election was on the minds of those at the Beverly Hilton, with many winners giving acceptance speeches calling for tolerance and unity.
Screen legend Meryl Streep took Trump to task in an emotional speech as she accepted a lifetime achievement award.
"Hollywood is crawling with outsiders and foreigners," she told the president-elect. "If you kick 'em all out, you'll have nothing to watch but football and mixed martial arts, which are not the arts."
She tore strips off Trump for the infamous campaign speech during which he did a decidedly unflattering impression of disabled reporter Serge Kovaleski -- the Republican president-elect denies mocking the man.
"It was that moment when the person asking to sit in the most respected seat in our country imitated a disabled reporter -- someone he outranked in privilege, power, and the capacity to fight back. It kind of broke my heart when I saw it," she said.
"I still can't get it out of my head because it wasn't in a movie. It was real life. And this instinct to humiliate, when it's modelled by someone in the public platform, by someone powerful, it filters down into everybody's life, because it kind of gives permission for other people to do the same thing."
"Disrespect invites disrespect. Violence incites violence," she said.
"When the powerful use their position to bully others, we all lose."
She urged the "principled press to hold power to account, to call them on the carpet for every outrage," to cheers from the floor.
She also spoke of the privilege of being given the chance to act for a living and remembered her friend, "Star Wars" actress Carrie Fisher, who died after Christmas, one day before her mother Debbie Reynolds.
"As my friend, the dear departed Princess Leia, said to me once: take your broken heart, make it into art."
Streep was nominated for best actress in a musical or comedy film at the glitzy ceremony at the Beverly Hilton Hotel for her performance in Stephen Frears's "Florence Foster Jenkins" but lost out to Emma Stone.
The annual DeMille award honors those who have made "outstanding contributions to the world of entertainment."