Guettard was born at Etampes in France. After a training in medicine and chemistry, he worked under the royal patronage of the duc d'Orléans from 1747 as keeper of his natural-history collection. Following the duc's death (1752) he continued this work under the patronage of his son.

In 1751 he made a crucial observation that upset the neptunism theories of Abraham Werner and his followers. While traveling through the Auvergne region he noticed an abundance of hexagonal basalt rocks and, exploring the region, identified the surrounding mountain peaks as the cones of extinct volcanoes (which would explain the presence of basalt). However, Werner's theory stated that all volcanic activity is recent, only occurring after the land has completely emerged from the oceans. Therefore, according to Wernerian theory, no volcanoes as ancient as the Auvergne ones should exist. Guettard published his findings in 1752 in his memoir, On Certain Mountains in France which once have been Volcanoes. He later changed his mind, distinguishing basalt from lava as it was not to be found among the recent volcanoes. He also observed the lack of vitrification found in basalt, then taken to be a sure sign of volcanic origin, and explained its formation by crystallization from an aqueous fluid.

Guettard was the first to map France geologically, publishing in 1780 his Atlas et description minéralogiques de la France (Mineralogical Atlas and Description of France). In the preparation of this he discovered (1765) a source of kaolin in Alençon, which made possible the production of the celebrated Sèvres porcelain.