Whittington was born at Handsworth in Yorkshire. After gaining his PhD from the University of Birmingham, he spent the years of World War II teaching in the Far East, first at the University of Rangoon, Burma, and for the rest of the war at Ginling College, West China. He returned to Birmingham in 1945 but moved to Harvard as curator of vertebrate paleontology at the Museum of Comparative Zoology. In 1966 Whittington left America for the post of Woodward Professor of Geology at Cambridge, a position he held until his retirement in 1983.

From the early 1960s Whittington devoted the bulk of his time to the study of the Burgess Shale fossils, discovered and described by C. D. Walcott earlier in the century. He made two expeditions to the site in 1966 and 1967 and recruited two assistants, Derek Briggs and Simon Conway Morris, to help him reexamine the entire collection.

Whittington's first report, published in 1971, was devoted to Marella splendens, identified by Walcott as a trilobite, a primitive and long-extinct arthropod. Whittington, after four years' work on several thousand specimens, found too many uncharacteristic trilobite features to be happy with Walcott's classification. He compromised by calling it Trilobitoidea (trilobite-like). His suspicion that many of Walcott's arthropods had been wrongly classified were increased when Whittington next looked at the subject of his 1975 monograph, Opabinia. As he could find no jointed appendages it was clear to Whittington that Opabinia could not be an arthropod. What its affinities were, however, remained uncertain.

By the time he came to deal in 1985 with Anamalocaris he could state confidently that it was no arthropod but “the representative of a hitherto unknown phylum.” Whittington and his colleagues went on to identify ten invertebrate genera “that have so far defied all attempts to link them with known phyla.”

Whittington's labors thus presented a dramatic new picture. The Cambrian is now seen as a period in which many new complex species suddenly appear. Further, relatively few of these seemingly advanced groups lasted beyond the Cambrian. The full significance of Whittington's work has yet to be worked out.