Fesch was a Corsican and the half brother of Napoleon's mother. After studies at the Seminary of Aix (1781–86) he became archdeacon of the cathedral chapter of his native city of Ajaccio. During the French Revolution, the Bonaparte family opposed the Corsican revolution of Pasquale Paoli, a native revolutionary leader, and Fesch was forced to join them in emigration to Toulon, Fr., in 1793. Soon after, he left the church and made a considerable fortune through business ventures and accompanied Napoleon to Italy as a supply contractor (1795–97).

Fesch returned to the church in 1800 and two years later was appointed archbishop of Lyon. In 1803 he received his cardinal's hat and journeyed to Rome as French ambassador. In this post, Fesch, often without enthusiasm, was forced to try to work out the difficulties between imperial policies and papal resistance. Increasingly he became estranged from this aspect of Napoleon's designs. In 1809, after Napoleon had virtually imprisoned the pope, Fesch refused to accept the archbishopric of Paris as a protest gesture. In 1811 he opened a council of the Gallican (or French national) church with a forceful declaration of fidelity to the papacy. This indiscretion caused Fesch to have to retire to Lyon and, when the empire fell, to Rome. He lived the remainder of his life still archbishop of Lyon, for the pope would not comply with French demands that he be deposed.