Mercati was born in Rome, the son of Pietro Mercati, physician to Popes Pius V and Gregory XIII. He was educated at the University of Pisa, where he took degrees in medicine and philosophy. He was interested in natural history, mineralogy, palaeontology, medicine, and botany, and produced a book on these subjects entitled the Metallotheca, which was not published until 1717.

Amongst other things, Mercati collected prehistoric stone tools along with fossils and minerals. These, in conjunction with his classical education and the growing Vatican Library collection of ethnographic artefacts from Asia and America, enabled him to include in the Metallotheca one of the first accounts of the manufacture and use of polished stone axes, flint arrowheads, and stone blades.

David Clarke describes Mercati as "the archaeological counterpart of Cardano in mathematics, Vesalius in anatomy, Galileo in the physical sciences and Copernicus in astronomy."