St. John served as a Republican in the Kansas Senate during the 1873-1874 term. A supporter of women's rights and an avid advocate of the government restriction of alcohol, he was elected governor of Kansas in 1878 as a Republican. During his first administration (1879-1881), he used his oratorical skills and political stature to persuade voters to adopt an amendment to the state constitution that banned the manufacture and sale of alcohol for consumption. St. John was reelected in 1880 and spent his second term primarily trying to ensure an effective enforcement of the prohibition on alcohol. Kansas voters denied him a third term in 1882 because of traditional opposition to third terms, reaction against prohibition in some quarters, controversy over his alleged support of railroad corporations, and opposition from political foes. Prohibition, however, remained the law in Kansas.

Animosity over St. John's defeat-the first for a Republican gubernatorial candidate in Kansas-led to his split with the Republican party. Thereafter, he dedicated himself to promoting the cause of prohibition on the lecture circuit. In 1884 the National Prohibition party nominated him for president of the United States. His campaign focused on the pivotal state of New York, where he received over 25,000 votes, primarily from wayward Republicans. Besides the strength of the Prohibitionist vote, the election in New York involved other unusual factors: the defection of some reform-minded Republicans (called "Mugwumps") to Grover Cleveland, the Democratic standard-bearer; the reaction against an anti-Catholic slur made by a key supporter of James Blaine, the Republican nominee; and, bad weather on voting day in upstate Republican-dominated districts. Together, those factors allowed Cleveland to carry New York by a slim plurality of 1,149 votes. New York's electoral votes proved to be the Democrat's margin of victory in the electoral college tally.