Jeffreys was born in Birtley in the northeast of England and educated in Newcastle upon Tyne and at Cambridge University. After graduating in 1913 he was made a fellow of his college. He was reader in geophysics from 1931 to 1946 before being elected to the Plumian Professorship of Astronomy and Experimental Philosophy where he remained until his retirement in 1958.

In 1924 Jeffreys produced one of the fundamental works in geophysics of the first half of the 20th century, The Earth: Its Origin, History, and Physical Constitution. In this he argued forcibly against Alfred Wegener's proposed theory of continental drift. He demonstrated that the forces proposed by Wegener were inadequate. This did much to inhibit interest and research into drift theory for a while but much new evidence in its favor has since been uncovered.

Jeffreys was also joint author, with Keith Bullen, of the Seismological Tables (1935). These, more frequently known as the JB Tables, were revised in 1940 and are the present standard tables of travel times of earthquake waves. They allow observers to determine from the elapsed time between the arrival of the primary (P) waves and the secondary (S) waves the distance between the observer and the earthquake.

Jeffreys's work in astronomy included studies on the origins of the universe. He developed James Jeans's theory of tidal evolution. He also devised models for the planetary structure of Jupiter, Saturn, Uranus, and Neptune.

He was knighted in 1953.