William was born December 14, 1859, in Chillicothe, Ohio. Little is known of his early schooling but he learned idiomatic German from schoolmates. When 17, he entered the U.S. Naval Academy, where he studied marine biology, graduating in 1880. He then was assigned to the ship Powhatan for a cruise in the tropics. In 1883, he entered Yale for advanced work in botany. In 1885, he registered at Harvard for marine zoology. Afterwards he went on a cruise around Cape Horn and into the South Pacific, focusing on botany and ethnology. On his return he taught languages at Annapolis for two years. During the years from 1891 to 1892, while off duty, he was in South America as commissioner to Peru and Bolivia for the Chicago Columbian Exhibition, chiefly devoting his attention to ethnology. Returning to the Navy in 1883, he served in the Spanish-American War and subsequently for a year as vice-governor of Guam. While in Guam he began the investigations that led to his Useful Plants of the Island of Guam and The Chamorro Language of the Island of Guam, both published in 1905. In 1902, he resigned from the Navy and became an assistant botanist in the Office of Economic and Systematic Botany of the Bureau of Plant Industry, U.S. Department of Agriculture, continuing with impressive works like Cactaceae of Northeastern and Central Mexico (1909). In 1915, he was promoted to economic botanist, his title to the end of his life. In 1920, George Washington University awarded him a PhD degree.

On March 17, 1924, he was stricken by a paralytic stroke from which he never recovered, although he continued working, dictating his books and maintaining his correspondence. He died January 10, 1926, a highly respected botanist, ethnologist, and linguist.

Two genera, Saffordia and Saffordiella, were named for him, as well as 16 species, the first being Vicia saffordii and the last Dianella saffordii.

He was elected to the Washington Biologists' Field Club in 1901 and was active throughout his life.