Born in Havana, Padura took a degree in Latin American literature at the University of Havana.

In 1980 he first came to prominence as an investigative journalist in a literary magazine called Caimán Barbudo, a well-established publication that is still in print today. He subsequently became known as an essayist and a writer of screenplays and in particular, detective novels.

He wrote his first short novel between 1983 and 1984, Fiebre de caballos (Horse Fever), which was basically a love story. He then spent the next six years continuing to work as a journalist, reporting on a wide range of cultural and historical topics. However around this time he began to write his first novel featuring Mario Conde, and while he was writing it, he realised how fundamental his years as a journalist were to his development as a writer. Firstly it gave him a whole new experience of the country, and secondly, it consequently changed his style with respect to his first book.

Padura is best known in the English-speaking world for his quartet of detective novels featuring lieutenant Mario Conde, Las cuatro estaciones (The four seasons). These have recently started to be published in English translation. Mario Conde is a cop who would rather be a writer, and admits to feelings of "solidarity with writers, crazy people, and drunkards". The novels are:

• Pasado perfecto ("Havana Blue", 2007), 1991
• Vientos de cuaresma ("Havana Yellow", 2008)), 1994
• Mascaras ("Havana Red", 2005), 1997
• Paisaje de otoño ("Havana Black", 2006), 1998.

These books are set respectively in winter, spring, summer and autumn (Vientos de cuaresma literally means "Winds of Lent", and Paisaje de otoño, Autumn landscape). Paisaje de otoño won the 1998 Premio Hammett of the Asociación Internacional de Escritores Policiacos (International Association of Crime Writers); this prize should not be confused with the similarly named Hammett Prize given by the North American branch of the organization, which is restricted to U.S. and Canadian authors. Padura has published two subsequent books featuring Conde, the novella Adiós Hemingway (Padura’s first book to be translated into English, in 2005), and a recent novel La neblina del ayer (The Fog of Yesterday). The Havana-Cultura website comments on the similarities and differences between Padura and Hemingway and how they might explain his decision to feature the expatriate American in Adiós Hemingway.

Padura's books are also available in French (including all the books featuring Conde), Italian, Portuguese, German and Danish.

Padura's novel El hombre que amaba a los perros (The Man Who Loved Dogs) deals with the murder of Leon Trotsky and the man who assassinated him, Ramon Mercader. At almost 600 pages in length it is his most accomplished work and the result of more than five years of meticulous historical research.

The novel, published in September 2009, attracted a lot of publicity mainly because of its political theme. The main argument of the author in the novel seems to be that Stalin betrayed socialism and destroyed the hope of creating a utopian society in the 20th century. It leaves open the possibility that such a society might still be possible in the 21st.