Mazzarino was born at Catania. As a scholar and faculty member of the University of Catania and University of Rome La Sapienza, Mazzarino was viewed as one of Italy's leading historians. His influential book La fine del mondo antico (1959) examined the death of Rome as a result of decadence. The book was widely read among non-specialists as well, and has been translated into several languages. Mazzarino's primary historical contributions covered subjects such as the 4th century economy, classical historiography, and various aspects of the Roman Empire.
As a Marxist, he blamed the same decadence for the woes of the modern world.
As of 2007, his main and fundamental works are being newly issued by Bollati Boringhieri, a renowned Italian scientific publisher in Turin.