Duchesne was educated at Loudun and Paris and devoted his early years to studies in history and geography. His first work, Egregiarum seu Selectarum Lectionum et Antiquitatum Liber (1602; “Andreas Querneus' Book of Extraordinary or Select Readings and Antiquities”), drew attention to his great erudition. Later, through the influence of the Cardinal de Richelieu, he was appointed historiographer and geographer to the king.

Duchesne's numerous works include general histories, genealogies, and family histories, as well as many folio volumes of manuscript extracts. Among the more noteworthy are Historiae Normannorum Scriptores Antiqui (1619; “Ancient Writers of the History of the Normans”), now the only source for some of the texts, and Historiae Francorum Scriptores, 5 vol. (1636–49; “Writers of the History of the Franks”), a projected 24-volume comprehensive collection of narrative sources of French history, of which only five volumes were written (the last three by Duchesne's son François).