The son of wealthy Burgundian landowners, Buffon was born in Montbard; he studied law at Dijon and medicine at Angers. After traveling in Italy and England, he inherited his mother's estate upon her death in 1732. The estate flourished under his direction, benefitting from Buffon's knowledge of sylviculture and the ironworks he installed, thus allowing him to concentrate upon scientific matters.

He began by translating S. Hales's Vegetable Statics (1735) and Newton's The Method of Fluxions (1740) into French. In 1739 he was appointed keeper of the Jardin du Roi, a post he occupied until his death. Buffon restored, extended, and embellished the institution, which was renamed as the Natural History Museum during the Revolution.

Buffon began work on his Histoire naturelle, a work that would dominate the rest of his life and which would eventually run to 44 volumes. The completed Histoire consisted of:

Vols. 1–15. Quadrupeds, 1749–67, with the assistance of Louis Daubenton who provided the anatomical details.

Vols. 16–24. Birds, 1770–83, with the assistance of the Abbé Bexon and G. de Montbeillard.

Vols. 25–31. Supplementary Volumes. These deal mainly with the quadrupeds, but Vol. 5 (1778) contains Buffon's important Epochs of Nature.

Vols. 32–36. Minerals, 1783–88.

The final 8 volumes, Reptiles (2 vols., 1788–89), Fish (5 vols., 1798–1803), and Cetacea (1804) were prepared by E. de Lacepede.

Vol. 1 contained an influential Preliminary Discourse. Nature, Buffon argued, was a continuum, and any attempts to divide it into apparently natural classes such as cats and dogs were misguided. Only individuals existed in nature; the rest, genera, species, classes and orders were bogus. In accordance with such views Buffon moved in the Histoire, quite artificially, from the familiar to the unfamiliar. He began with Man and familiar domestic animals such as dogs, horses, and cows, before moving on to savage animals. The horse was followed by the dog, not the zebra.

In later volumes of the Histoire Buffon modified these initial extreme views. He conceded that “two animals belong to the same species as long as they can perpetuate themselves,” and also accepted that there did seem to be, beneath superficial differences, “a single plan of structure” present in all quadrupeds. This did not, however, imply a common descent. If, he argued, the ass was derived from the horse, where were the intermediate forms?

Buffon took a bolder line in his Epochs of Nature. He argued against the traditional Biblical chronology of about 6000 years for the Earth's age, claiming instead a period of 78,000 years between the formation of the solar system and the emergence of humans. The estimates were based upon assumptions concerning the rate at which hot bodies of known size and temperature cooled. His calculations allowed him to go further and predict that temperatures will continue to fall, and when they reach 1/25th of the present temperature after 93,000 years, life on Earth will be extinguished.