He was born François Charles Mauriac in Bordeaux, France. He studied literature at the University of Bordeaux, graduating in 1905, after which he moved to Paris to prepare for postgraduate study at the École des Chartes. He was opposed to the rule in Vietnam, and strongly condemned the use of torture by the French army in Algeria. He also published a series of personal memoirs and a biography of Charles de Gaulle.

On 1 June 1933 he was elected a member of the Académie française, succeeding Eugène Brieux.

In 1952, he won the Nobel Prize in Literature "for the deep spiritual insight and the artistic intensity with which he has in his novels penetrated the drama of human life". He was awarded the Grand Cross of the Légion d'honneur in 1958. Mauriac's complete works were published in twelve volumes between 1950 and 1956. He also encouraged Elie Wiesel to write about his experiences as a Jew during the Holocaust, and wrote a foreword in Elie Wiesel's book, Night.

Mauriac had a bitter public dispute with Roger Peyrefitte, who criticised the Vatican in books such as Les Clés de saint Pierre (1953). Mauriac threatened to resign from the paper he was working with at the time (L'Express) if they did not stop carrying advertisements for Peyrefitte's books. The quarrel was exacerbated by the release of the film adaptation of Peyrefitte's Les Amitiés Particulières and culminated in a virulent open letter by Peyrefitte in which he accused Mauriac of homosexual tendencies and called him a Tartuffe.

Mauriac also had a bitter dispute with Albert Camus immediately following the liberation of France in World War II. At that time, Camus edited the resistance paper (now an overt daily) Combat while Mauriac wrote a column for Le Figaro. Camus said newly liberated France should purge all Nazi collaborator elements, but Mauriac warned that such disputes should be set aside in the interests of national reconciliation. Mauriac also doubted that justice would be impartial or dispassionate given the emotional turmoil of liberation.

François Mauriac died in Paris on 1 September 1970 and was interred in the Cimetière de Vemars, Val d' Oise, France.

He was the father of writer Claude Mauriac and grandfather of Anne Wiazemsky, a French actress and author who worked with and married French director Jean-Luc Godard.