William Mansfield Clark was born in Tivoli, New York. He studied with Leverett Mears at Williams College in Williamstown, Massachusetts, and received a B.A. in 1907 and an M.A. in 1908. Clark then moved to Johns Hopkins University as a student of Harmon Morse and earned his Ph.D. in 1910. While at Johns Hopkins, Clark spent his summers at the recently established chemistry laboratory at Wood's Hole, Massachusetts, where he served as an assistant to Carl Alsberg and later, Donald D. Van Slyke. Immediately after receiving his Ph.D., Clark joined the dairy division of the U.S. Department of Agriculture as a research chemist. Before he resigned in 1920, he worked on a variety of problems in dairy bacteriology, and, with his colleague Herbert A. Lubs, developed and defined the concept of pH, resulting in Clark's seminal book, The Determination of Hydrogen Ions.
Remaining in government service, Clark took a position as head of the Division of Chemistry at the Hygiene Laboratory of the U.S. Public Health Service in 1920, where he remained until 1927. There, he published a series of papers on oxidation reduction. In 1927, he accepted an appointment as DeLamar Professor of Physiological Chemistry at the Johns Hopkins University School of Medicine, where he continued his research on oxidation-reduction potentials. During his 25 years at Johns Hopkins, Clark expanded his research program into ligand and metalloporphyrin systems, and he developed the concept of a "chemical continuum." In 1952, Clark retired from Johns Hopkins and was appointed DeLamar Emeritus Professor and research professor of chemistry.
Clark received a number of honors and awards during his career, including election to the National Academy of Sciences (1928) and the American Philosophical Society (1939) and election as president of the Society of American Bacteriologists and of the American Society of Biological Chemists (1933 and 1934). He was awarded the William H. Nichols Medal of the New York Section, American Chemical Society (1936); the Borden Award (1944); the President's Certificate of Merit (1948); the Passano Award (1957); and the Award of Merit of the Maryland Section, American Chemical Society (1963). Clark also served on the editorial board of the Journal of Biological Chemistry from 1933 until 1952.