His 1768 book on physiocracy (Physiocratie, ou Constitution naturelle du gouvernement le plus avantageux au genre humain) advocated low tariffs and free trade among nations, deeply influenced Adam Smith of Scotland.

He was invited in 1774 by King Stanisław August Poniatowski (Stanislaus II Augustus) of the Polish–Lithuanian Commonwealth to help organize that country's educational system.

He and his son Eleuthère were among those who physically defended Louis XVI and Marie Antoinette from a mob besieging the Tuileries Palace in Paris during the insurrection of 10 August 1792.

Condemned to the guillotine during the Reign of Terror, du Pont was awaiting execution when Robespierre fell on 9 thermidor an IV (27 July 1794), and he was spared.

After du Pont's house was sacked by a mob during the events of 18 Fructidor V (4 September 1797), he, his sons and their families immigrated to the United States in 1799.

In the United States, du Pont developed strong ties with industry and government, in particular with Thomas Jefferson, with whom he had been acquainted since at least 1787 and who had referred to him as "one of the very great men of the age" and "the ablest man in France.

He was the originator of an idea that eventually became the Louisiana Purchase, as a way to avoid French troops landing in New Orleans, and possibly sparking armed conflict with U.S.