The seminary was founded in 1889 by Fr John R. Slattery of the Mill Hill Missionaries, a English Catholic society of apostolic life.

[1][2] Charles Uncles, the first African-American Catholic priest trained and ordained in the United States and a cofounder of the Josephites, studied at Epiphany.

[1] After Uncles, the young priest Dominic James Manley, also a Josephite cofounder, served as president from 1889 to October 1893.

[4] At Epiphany, he was succeeded by Fr Robert J. Carse, who went on to become pastor of St. Patrick Parish in St. Charles, Illinois, for 41 years and died in 1950.

For several decades in the early to late 20th century, racial politics led to the seminary being closed to most African Americans.