Maclure was born at Ayr in Scotland. After a brief visit to New York in 1782 he began active life as a partner in a London firm of American merchants. In 1796 business affairs took him to Virginia, U.S.A., which he thereafter made his home. In 1803 he visited France as one of the commissioners appointed to settle the claims of American citizens on the French government; and during the few years then spent in Europe he applied himself with enthusiasm to the study of geology.
On his return home in 1807 he commenced the self-imposed task of making a geological survey of the United States. Almost every state in the Union was traversed and mapped by him, the Allegheny Mountains being crossed and recrossed some fifty times. The results of his unaided labours were submitted to the American Philosophical Society in a memoir entitled Observations on the Geology of the United States explanatory of a Geological Map, and published in the Society's Transactions (vol. iv. 1809, p. 91) together with the first geological map of that country. This antedates William Smith's geological map of England by six years. In 1817 Maclure brought before the same society a revised edition of his map, and his great geological memoir was issued separately, with some additional matter, under the title Observations on the Geology of the United States of America. Subsequent survey has corroborated the general accuracy of Maclure's observations.
In 1812, while in France, Maclure became a member of the newly founded Academy of Natural Sciences of Philadelphia (ANSP). In 1817 Maclure became president of the ANSP, a post he held for the next twenty-two years.
In 1819 he visited Spain, and attempted, unsuccessfully, to establish an agricultural college near the city of Alicante. Returning to America in 1824, he settled for some years at New Harmony, Indiana, and sought to develop his scheme of the agricultural college. Failing health ultimately constrained him to relinquish the attempt, and to seek (in 1827) a more congenial climate in Mexico. There, at San Angel, he died.