The Skirball Museum has a long history as one of the oldest repositories of Jewish cultural artifacts in America. The first stage in the museum's development lasted for nearly a century, beginning when Hebrew Union College (HUC) opened in Cincinnati, Ohio in 1875 and over time began accepting donations of Judaic objects and books. In 1913 the College's Union Museum was founded with the assistance of the National Federation of Temple Sisterhoods, becoming the first formally established Jewish museum in the United States. In the 1920s, the collections rapidly expanded with the purchase of several significant private collections of Judaica, including those of Salli Kirchstein, Joseph Hamburger, and Louis Grossman. In 1950, HUC merged with the Jewish Institute of Religion (JIR).
In 1990, The Skirball Museum Cincinnati opened in the newly renovated Mayerson Hall, presenting its core exhibit An Eternal People: The Jewish Experience, comprised of seven thematic galleries that portray the cultural, historical, and religious heritage of the Jewish people.