Educated by Jesuits, du Cange studied law and practiced for several years before assuming the office of Treasurer of France. Du Cange was a busy, energetic man who pursued historical scholarship alongside his demanding official duties and his role as head of a large family.
Du Cange's most important work is his Glossarium mediae et infimae Latinitatis (Glossary of medieval and late Latin, Paris, 1678). This work, together with a glossary of medieval and late Greek that he published ten years later, has gone through numerous editions and revisions and is still consulted frequently by scholars today. Du Cange's pioneering work distinguished medieval Latin and Greek from their earlier classical forms, marking the beginning of the study of the historical development of languages.
Du Cange mastered languages in order to pursue his main scholarly interests, medieval and Byzantine history. He corresponded voluminously with his fellow scholars. His great historical and linguistic knowledge was complemented by equally deep learning in archaeology, geography and law. In addition to his glossaries, he produced important new editions of Byzantine historians and a number of other works. His extensive history of Illyria was not published until 1746 by Joseph Keglevich, who partially corrected it.
Du Cange is one of the historians Edward Gibbon cites most frequently in his Decline and Fall of the Roman Empire. In one footnote he calls du Cange "our sure and indefatigable guide in the Middle Ages and Byzantine history."