Del Rio was born in the Spanish capital Madrid and graduated in Spain in 1781 before going on to study in France, England, and Germany, where he was a pupil of Abraham Werner at the Freiberg Mining Academy. He had been chosen by Charles III to acquire the new scientific learning and to introduce it into the Spanish empire in order to develop and modernize the mining industry. Consequently he was sent to Mexico City to become, in 1794, professor of mineralogy at the School of Mines set up by Fausto D'Elhuyar. While in Mexico he published the Elementos de orictognosia (1795; Principles of the Science of Mining), which has some claim to being the first mineralogical textbook published in the Americas. He was forced into exile in the period 1829–34 after Mexico's war of independence but on his return he tried to reestablish the scientific tradition he had first introduced.

As a scientist he is best remembered for his independent discovery of the element vanadium in 1801. He had found what he took to be a new metal in some lead ore from the Mexican mines and named it ‘erythronium’ (from the Greek erythros, red) as its salts turned red when ignited. However, he failed to press his claim, being persuaded by other scientists that it was probably a compound of lead and chromium. The Swedish chemist Nils Gabriel Sefström (1787–1845) rediscovered the metal in 1830 and named it vanadium. Its identity with Del Rio's erythronium was demonstrated by Friedrich Wöhler in 1831.