In 1799 Daniel and Rebecca Boone and many members of their extended families left Kentucky and settled on the Missouri River. Rebecca's first cousin, David Bryan, acquired and settled on the Spanish land grant of Jeremiah Groshong in 1800. Daniel and Rebecca were buried in the cemetery on this land. Gottfried Duden lived near Dutzow between 1824 and 1827. His letters to Germany inspired the large German migration to this area. The letters have been published as Report on a Journey to the Western States of North America. After being part of St. Charles and Montgomery Counties in the Louisiana and Missouri Territories, Warren County was set apart by the State Legislature in 1833. Warrenton was established as the county seat in 1835.
The Museum and Library was built in 1982. In 2009, the Society received a bequest from R. Stuart Hummel of Sonoma, CA to be used for an addition to the Museum. The Hummel Addition, which doubled the size of the building, opened in May 2012. The museum's newest exhibit focuses on the history of the Central Wesleyan College and Orphan Home.