At the time, there was a debate as to whether the Earth was wider around the equator or around the poles. The King of France and the French Royal Academy of Sciences sent two expeditions to determine the answer; one was sent to Lapland (this expedition included the Swedish physicist Anders Celsius) and another to Ecuador. La Condamine was in the Ecuadorian group, which included Louis Godin and the mathematician Pierre Bouguer.

The Ecuadorian expedition left France in May 1735. They landed in Colombia and traveled overland to Panama, then sailed to Ecuador. La Condamine traveled through rainforests with Pedro Vincente Maldonado, a local governor and scientist-mathematician. They sailed up the Esmeraldas River and then climbed up the Andes Mountains. They arrived in Quito, Ecuador, on June 4, 1736. They finished their measurements by 1739, measuring the length of an arc of one degree at the equator, but they got word that the Lapland expedition had already finished their work and had proven that the Earth is flattened at the poles.

La Condamine remained in South America for four more years, doing scientific work and mapping some of the Andes and much of the Amazon River. He returned to France by climbing the Andes Mountains and rafting down the Amazon River. He arrived in Paris in 1745, 10 years after he left France.

La Condamine's journal of his 10-year adventure, "Journal du Voyage fait par l'ordre du Roi á l'equateur," was published in 1751. La Condamine is also said to have thought of the idea of introducing vaccinations for smallpox in Europe since he had suffered from smallpox as a child (Edward Jenner later developed the actual vaccine).

The Crater La Condamine, a 67-kilometer diameter crater on the moon, was named for La Condamine.