Born in Brattleboro, Vermont, in 1846, William R. Mead had an early exposure to the arts through his brother, a sculptor, and his sister, a painter. He studied at Norwich University and Amherst College, graduating from the latter in 1867. Mead then moved to New York to work for a year with an engineer and for two years as an apprentice in the office of Russell Sturgis. Following his apprenticeship, he joined his brother in Florence and attended classes at the Academia delle Belli Arti.
Mead returned to New York, and by 1880 his enduring partnership with Charles F. McKim and Stanford White had been formed. After designing a number of east-coast homes in the shingle style, the three men came to embody the new neoclassical principles which were celebrated at the World's Columbian Exposition in 1893. One of their contributions, the Agriculture Building, received its highly lauded decoration from George Maynard. Other important McKim, Mead and White projects were the Villard Houses, Washington Square Arch, Columbia University, the Brooklyn Museum, and Pennsylvania Station, all in New York. Among the partners, Mead was thought of as being the most practical and moderate, a directorial and executive force.
After the deaths of McKim and White, Mead ran the firm until his retirement in 1920. He spent much of his remaining life abroad, dying in Paris in 1928. For the last 18 years of his life he was president of the American Academy in Rome.