La Harpe and about forty others sailed from La Rochelle, France, on the ship called "Victoire" in 1718. They landed at Dauphin Island (off the coast of what is now Alabama), in the late summer of 1718. By 1719, they established Fort Saint Louis de los Cadodaquious (also called San Luis de Cadodachos and Fort Breton) and then explored up the Mississippi, Red, and Sulphur rivers.

La Harpe returned to France in 1720, but sailed for the Texas coast (Matagorda Bay) on the ship "Subtile" in 1721. He was supposed to have established a settlement at Saint Bernard, but had mistakenly sailed to Galveston Bay. The local Indians opposed this and La Harpe did not settle the area.

La Harpe explored the area up the Arkansas River in 1722, trying to establish trade routes with the Spanish in the southwest; he was unsuccessful and in 1723, was fired by the Company of the Indies, which had subsidized his expeditions. La Harpe then returned to France, and never set foot in America again.

He wrote an account of his adventures, called "Journal Historique Concernant l'Établissement des Français à la Louisiane," published in 1831, but historians are uncertain as to the accuracy of his accounts.