The moviemaker took home the prestigious honour for his silent movie The Artist, seeing off competition from Hollywood heavyweights Woody Allen (Midnight in Paris) and Martin Scorsese (Hugo), David Fincher (The Girl with the Dragon Tattoo) and Alexander Payne (The Descendants).
The trophy launches Hazanavicius into pole position to win an Academy Award in February (12), as the winner of the DGA has gone on to win the Best Director Oscar all but six times since the guild began handing out awards in 1949.
Accepting his prize, Hazanavicius said, "It's maybe the highest recognition I could hope for. Maybe you noticed, but I'm French. I have an accent. I have a name that is very difficult to pronounce. I'm not American and I'm not French, actually - I'm a film-maker...
"I feel like I'm being accepted by you, not as Americans, but as film-makers. This is really very moving and very touching for me."
The guild's choice for Best Director has also been the person behind the Oscars' Best Picture 50 times - in 2011, Tom Hooper went on to land the Best Director and Best Picture honour at the Academy Awards for The King's Speech.
The Artist has been nominated in 10 categories, including Best Director and Best Picture, at the upcoming Academy Awards.