Born in the capital city of Forlì, in the Romagna region, Flavio was well schooled from an early age, studying under Ballistario of Cremona.

After his patron's death, Flavio was employed by his papal successors, Nicholas V, Callixtus III and the humanist Pius II.

Unlike medieval geographers, whose focus was regional, Biondo, taking Strabo for his model, reinstated the idea of Italy to include the whole of the peninsula.

Flavio's greatest work is the Historiarum ab Inclinatione Romanorum Imperii (Venice, 1483), a history of Europe in thirty-two books, from the plunder of Rome in 410 by the Visigoths to contemporary Italy (1442).

Using only the most reliable and primary sources, it used a three-period framework, with Italy reviving in Biondo's own time and breaking free of earlier trends.