He is remembered for Williston's law, which states that parts in an organism, such as arthropod limbs, become reduced in number and specialized in function through evolutionary history.

As a young child, Williston's family travelled to Kansas Territory in 1857 under the auspices of the New England Emigrant Aid Company to help fight the extension of slavery.

Although never employed as a professional entomologist, Samuel W. Williston was a Fellow of the Entomological Society of America since 1915,[6] and was well-renowned specialist on the taxonomy and systematics of flies (Diptera).

Williston noticed that, over evolutionary time, the modular and serially repeated parts distinguishing animal groups exhibited trends in numbers and types.

For instance, a study of the evolution in the number of branchiostegal rays in osteichthyans has failed to support a generalized trend towards reduction.