Born to poor parents, he attended newly-founded Deerfield Academy and in 1821 was ordained as a Congregationalist pastor. A few years later he left the ministry to become Professor of Chemistry and Natural History at Amherst College. He held that post from 1825 to 1845, serving as Professor of Natural Theology and Geology from 1845 to his death in 1864. In 1845 Hitchcock became President of the College, a post he held until 1854. As president, Hitchcock was responsible for Amherst's recovery from severe financial difficulties. He is also credited with developing the college's scientific resources and establishing its reputation for scientific teaching.
In addition to his positions at Amherst, Hitchcock was a well-known early geologist. He ran the first geological survey of Massachusetts, and in 1830 was appointed state geologist of Massachusetts (he held the post until 1844). He also played a role in the geological surveys of New York and Vermont. His chief project, however, was natural theology, which attempted to unify and reconcile science and religion, focusing on geology. His major work in this area was The Religion of Geology and its Connected Sciences (Boston, 1851). In this book, he found somewhat tortured ways to make the Bible agree with the latest geological theories. For example, he knew that the earth was at least hundreds of thousands of years old, vastly older than the 6,000 years posited by Biblical scholars. Hitchcock actually found a way to read the original Hebrew so that a single letter in Genesis—a "v", meaning "afterwards"—implied the vast timespans during which the earth was formed.
Hitchcock left his mark in paleontology. He published papers on fossilized tracks in the Connecticut Valley, including Eubrontes and Otozoum, that were later associated with dinosaurs, though he believed, with a certain prescience, that they were made by gigantic ancient birds. In the Hitchcock Ichnological Cabinet he established a remarkable collection of fossil footmarks. His son, Edward "Doc" Hitchcock, named one of the earliest dinosaurs discovered in America, Megadactylus polyzelus. Later it was reclassified as the type specimen of Anchisaurus polyzelus (ACM 41109), a prosauropod.
As he had done research on the geologic lake which once filled the Connecticut River basin, this prehistoric lake was named after him.
His collections, a bust and portrait can be viewed at the Amherst College Museum of Natural History.