Buzzati was born at San Pellegrino, Belluno, in his family's ancestral villa. Buzzati's mother, a veterinarian by profession, was Venetian and his father, a professor of international law, was from an ancient Bellunese family. Buzzati was the second of his parents' four children. In 1924, he enrolled in the law faculty of the University of Milan, where his father once taught. As he was completing his studies in law, he was hired, at the age of 22, by the Milanese newspaper Corriere della Sera, where he would remain until his death. He began in the corrections department, and later worked as a reporter, special correspondent, essayist, editor and art critic. It is often said that his journalistic background informs his writing, lending even the most fantastic tales an aura of realism.

Buzzati himself comments on the connection (as cited by Lawrence Venuti):

During World War II, Buzzati served in Africa, as a journalist attached to the Regia Marina. After the end of the war, Il deserto dei Tartari was published Italy-wide and quickly brought critical recognition and fame to the author. He married Almeria Antoniazzi in 1964, which also marked the release of his last novel, Un amore. In 1972, Buzzati died of cancer after a protracted illness.

Buzzati began writing fiction in 1933. His works of fiction include five novels, theatre and radio plays, librettos, numerous books of short stories and poetry.

He wrote a children's book La famosa invasione degli orsi in Sicilia (translated by Frances Lobb into English as The Bears' Famous Invasion of Sicily). Lemony Snicket wrote an introduction and reader's companion to a 2005 English edition.

Also an acclaimed and exhibited artist, Buzzati also combined his artistic and writerly exploits into making a comic book based on the myth of Orpheus, Poema a fumetti.

The Tartar Steppe, his most famous novel, tells the story of a military outpost that awaits a Tartar invasion. In its sentiment and its conclusions, it has been compared to existentialist works, notably Albert Camus's The Myth of Sisyphus.

His writing is sometimes cited as magical realism, social alienation, and the fate of the environment and of fantasy in the face of unbridled technological progress are recurring themes. He has also written a variety of short stories featuring fantastic animals such as the bogeyman and, his own invention, the colombre (il colombre).