The victory for "Timbuktu" could propel it towards greater glory at the Oscars on Sunday, where it is nominated for the best foreign film award.
Filmmaker Abderrahmane Sissako, who won a César for best director among the film's haul of awards, said he wanted to show the residents of the ancient city struggling to maintain their daily lives in the face of the brutal rule of jihadists who seized a large portion of Mali's vast desert in 2012.
Most of the film had to be made in Sissako's native Mauritania as northern Mali, despite being freed from jihadist control by a French military intervention, remains an extremely dangerous place, especially for foreigners.
In his acceptance speech, Sissako - who became the first black African to win the best director César - praised French people for taking to the streets in their millions after the Islamist attacks in Paris last month that left 17 dead.
"France is a magnificent country because it is able to stand up to the horror and to the violence," he said.
"There is no clash of civilisations. There is a meeting of civilisations," he added.
American star Kristen Stewart also made history during the awards night, becoming the first US actress to scoop up the French film prize. She was awarded as best supporting actress for her role alongside Juliette Binoche in "Clouds of Sils Maria".
Directed by France's Olivier Assayas, 24-year-old Stewart plays the personal assistant to a star actress played by Binoche and follows their intense, sexually-charged relationship.
Stewart has spoken of how working with Binoche, one of France's leading ladies for three decades, was a privilege and as she mounted the stage in Paris on Friday she shouted "I love you Juliette" in French.
The best actor category saw Pierre Niney beat Gaspard Ulliel in a battle between two portrayals of legendary fashion designer Yves Saint Laurent. The two biopics were released within months of each other last year.
There was more American success when two-time Oscar winner Sean Penn - artfully dishevelled in a black suit and loosened tie - received a César lifetime achievement award to tumultuous applause from the audience at the Chatelet theatre.
Adele Haenel won the best actress award for romantic comedy "Love at First Fight" ("Les Combattants" in French).
The prize for best foreign film went to Xavier Dolan for "Mommy", the 25-year-old French Canadian director's fifth feature-length movie.
The audacious drama laced with wicked humour stars Anne Dorval playing a feisty mother grappling with a violent, bipolar son.