Born in Quebec City, Quebec, she was educated at a convent school and at Université Laval. It was at Laval that she met Jeanne Lapointe and Father Georges Lévesque, who encouraged her to write and, in 1959, to publish her first novel, La Belle Bête (trans. Mad Shadows) in 1959 when she turned 20. She has since written over 20 novels, several plays, collections of poetry and fiction, as well newspaper articles. Her works have been translated into numerous languages, including English and Chinese. With the support of the eminent American critic Edmund Wilson, Blais won two Guggenheim Fellowships.

In 1963, Blais moved to the United States, initially living in Cambridge, Massachusetts. There she met her partner, American artist Mary Meigs, and she later relocated to Wellfleet on Cape Cod. In 1975, after two years living in Brittany, she moved back to Quebec with her partner. For about twenty years she divided her time between Montreal, the Eastern Townships of Quebec and Key West, Florida.

Much of Blais' writing has been in the form of social commentary, with intermixed elements of good and evil in settings part real, and part fantasy. Her works lean toward the tragic, within a hostile society of vice and violence. The strength of Blais' writing ability is rewarding to the reader in spite of the darker aspects of her themes.

In 1972 she became a Companion of the Order of Canada.

Her works Le Sourd dans la ville (1979), Une Saison dans la vie d'Emmanuel (1965) and La Belle Bête (1959), have been adapted for the cinema, the latter by Canadian film director Karim Hussain in 2006.