As a boy Walcott discovered that he had a knack for finding fossils, particularly trilobites, and built up a collection of sufficient distinction that it was bought by Louis Agassiz for his museum at Harvard for a small fortune—about $70,000 in today's money. Although he had barely a high school education and was self taught in the sciences, Walcott became a leading authority on trilobites and was the first person to establish that trilobites were arthropods, the group that includes modern insects and crustaceans.

In 1879 he took a job as a field researcher with the newly formed United States Geological Survey and served with such distinction that within fifteen years he had risen to be its head. In 1907 he was appointed secretary of the Smithsonian Institution, where he remained until his death in 1927. Despite his administrative obligations, he continued to do fieldwork and to write prolifically. "His books fill a library shelf," according to Fortey. Not incidentally, he was also a founding director of the National Advisory Committee for Aeronautics, which eventually became the National Aeronautics and Space Agency, or NASA, and thus can rightly be considered the grandfather of the space age.