Born in Aubagne, he was educated by his uncle the abbé Jean-Jacques Barthélemy for a diplomatic career. After serving as secretary of legation in Sweden, in Switzerland and in the Kingdom of Great Britain, he was appointed Minister Plenipotentiary in Switzerland, in which capacity he negotiated the treaties of Basel with Prussia and Spain (1795).
Elected a member of the Directory in May 1797, through Royalist influence, he was arrested after General Augereau's anti-Royalist coup d'état of the 18 Fructidor (17 September 1797), and deported to French Guiana, but escaped and made his way to Suriname, then to the United States, and finally to Britain.
Barthélemy returned to France after Napoleon Bonaparte's 18 Brumaire coup, entered the Senate in February 1800 and contributed to the establishment of the Consulship for life and the First French Empire.
In 1814 he abandoned Napoleon, voted the Acte de déchéance de l'Empereur and took part in the drawing up of King Louis XVIII's Constitutional Charter and was named Peer of France. During the Hundred Days he lived in concealment, and after the Second Restoration obtained the title marquis, and in 1819 introduced a motion in the chamber of Peers tending to render the electoral law more aristocratic.