Born in Melrose, Massachusetts, Wright graduated from Lombard College in 1911; he gained his master's degree from the University of Illinois the following year and his doctorate from Harvard in 1916. He then worked as senior animal husbandman for the US Department of Agriculture and began his researches into the population genetics of guinea pigs. His first work aimed to find the best combination of inbreeding and crossbreeding to improve stock, this having practical application in livestock breeding. From this he also developed a mathematical theory of evolution.

His name is best known, however, in connection with the process of genetic drift, which is also termed the Sewall Wright effect. He demonstrated that in small isolated populations certain forms of genes may be lost quite randomly, simply because the few individuals possessing them happen not to pass them on. The loss of such characters may lead to the formation of new species without natural selection coming into operation. Wright held professorial positions at the University of Chicago and Edinburgh University and was emeritus professor at the University of Wisconsin.