Pitol was born into a family of Italian descent. His childhood was a difficult one, marked by his mother's death by drowning. He studied both literature and law at the National Autonomous University of Mexico in Mexico City (1950–55), and by 1960 he had begun working for Mexico's Ministry of Foreign Relations. Pitol served as a cultural attaché in Poland, Hungary, and France during the 1970s, traveled to Italy, the U.S.S.R., and China, and eventually became Mexico's ambassador to Czechoslovakia in the mid-1980s. He taught at the University of Veracruz, Xalapa, Mex. (1966–77), and the University of Bristol, Eng. (1971–72), and translated literary works from English and Polish.

Pitol wrote throughout his diplomatic career and became known for his short stories. Although his first published collection, Tiempo cercado (1959; “Corralled Time”), received little notice, later works firmly established his reputation. Vals de Mefisto (1984; “Dance of Mephisto”) won the Xavier Villaurrutia Prize, one of Mexico's highest literary awards.

A vibrant formal experimentation also ran throughout much of Pitol's writing, especially his longer works. The novel El tañido de una flauta (1972; “The Twang of the Flute”), set in New York and Europe, played with cinematic conventions, while El desfile del amor (1984; “The Parade of Love”) used a murder mystery as a framework to experiment with narrative perspective. His later works included memoirs that pushed the boundaries of the genre. El arte de la fuga (1996; “The Art of Flight”) recounted Pitol's childhood, his experiences as a writer in Mexico during the 1950s and '60s, and his work as a diplomat, but it also included literary analysis of books that Pitol found influential and an examination of the ongoing uprising by the Zapatista National Liberation Army in Chiapas. His El mago de Viena (2005; “The Magician of Vienna”) was also classified as a memoir, and it encompassed discursive explorations of literature, a complicated narrative framework, and a month's worth of Pitol's diary, all part of his continuing reflection on a lifetime spent as one of Mexico's most internationally known writers. For his body of work, Pitol was awarded the 2005 Cervantes Prize, the most prestigious literary award in the Spanish-speaking world, which was presented to him in 2006.