Nicollet showed promise in mathematics and astronomy early; he became a teacher of mathematics at the age of 19. In 1817 he began working with the scientist Pierre-Simon Laplace at the Paris Observatory, and in the 1820s he became a professor of mathematics at the Collège Louis-le-Grand in Paris.
In 1832 Nicollet immigrated to the United States after financial reverses in France. He lived first in New Orleans, Louisiana, and then settled in St. Louis, Missouri. With support from the wealthy Chouteau family of St. Louis, Nicollet in 1836–37 led an expedition that surveyed the sources of the Mississippi River. In 1838 he accepted a position with the U.S. Army Corps of Topographical Engineers, and in 1838–39 he led a government surveying expedition to map the region between the upper Mississippi and Missouri rivers, assisted by John C. Frémont. Nicollet later prepared a detailed map of the region and wrote a report on the expedition; these were published in 1843, after his death.