He traveled as a young man in the United States, ultimately settling in Ohio in 1815, where he made notable contributions to botany, zoology, and the study of prehistoric earthworks in North America.

He wrote prolifically on such diverse topics as anthropology, biology, geology, and linguistics, but was honored in none of these fields during his lifetime.

[11] By 14, he had taught himself Greek and Latin because he needed to follow footnotes in the books he was reading in his paternal grandmother's libraries.

When his ship Union foundered near the coast of Connecticut, he lost all his books (50 boxes) and all his specimens (including more than 60,000 shells).

[16] In 1817, his book Florula Ludoviciana [es] or A Flora of the State of Louisiana was strongly criticized by fellow botanists, which caused his writings to be ignored.

[17][18] In 1819, Rafinesque became professor of botany at Transylvania University in Lexington, Kentucky, where he also gave private lessons in French, Italian, and Spanish.

[30] After studying the specimens collected by the Lewis and Clark expedition, he assigned scientific names to the black-tailed prairie dog (Cynomys ludovicianus), the white-footed mouse (Peromyscus leucopus), and the mule deer (Odocoileus hemionus).

[35]In the third edition of On the Origin of Species published in 1861, Charles Darwin added a Historical Sketch that acknowledged the ideas of Rafinesque.

This included Walam Olum, a purported migration and creation narrative of the Lenape (also known by English speakers as the Delaware Indians).

Rafinesque claimed he had obtained wooden tablets engraved and painted with indigenous pictographs, together with a transcription in the Lenape language.

Rafinesque claimed the original tablets and transcription were later lost, leaving his notes and transcribed copy as the only record of evidence.

[citation needed] For over a century after Rafinesque's publication, the Walam Olum was widely accepted by ethnohistorians as authentically Native American in origin, but as early as 1849, when the document was republished by Ephraim G. Squier, Henry Rowe Schoolcraft, an ethnologist who had worked extensively in Michigan and related territories, wrote to Squier saying that he believed the document might be fraudulent.

[41] In the 1950s, the Indiana Historical Society published a "retranslation" of the Walam Olum, as "a worthy subject for students of aboriginal culture".

[42] Since the late 20th century, studies especially in linguistic, ethnohistorical, archaeological, and textual analyses suggest that the Walam Olum account was largely or entirely a fabrication.

[43] After the publication in 1995 of David Oestreicher's thesis, The Anatomy of the Walam Olum: A 19th Century Anthropological Hoax, many scholars concurred with his analysis.

[43] Rafinesque made a notable contribution to North American prehistory with his studies of ancient earthworks of the Adena and Hopewell cultures, especially in the Ohio Valley.

Only a few of his descriptions were published, with his friend John D. Clifford's series "Indian Antiquities", eight long letters in Lexington's short-lived Western Review and Miscellaneous Magazine (1819–1820).

All sites in Kentucky that were included by E. G. Squier and Davis in their notable Ancient Monuments of the Mississippi Valley (1848), completed for the Smithsonian Institution, were first identified by Rafinesque in his manuscripts.

Scientists were troubled that his theory of evolution – long before Darwin – seemed to be based more on his speculation and exaggerations than on solid research.

[52] John Jeremiah Sullivan's essay La-Hwi-Ne-Ski: Career of an Eccentric Naturalist, which appears in his 2011 collection, Pulphead, chronicles the life and times of Rafinesque.