[2] The county was organized February 14, 1845, and named for Major General John Sullivan of the American Revolutionary War.

[3] In 1682, René-Robert Cavelier, Sieur de la Salle claimed the territory west of the Mississippi River for France, which included present-day Sullivan County.

Twenty-one years later, the Sac (Sauk), Meskwaki (Fox), and Iowa Native American nations ceded their tribal land to the U.S. government under two treaties in August 1824.

Dr. Holland, a veteran of the Black Hawk War and practitioner of herbal medicine, and son staked their home sites at the Main Locust Creek Settlement near a place called Scottsville.

[5][6] Settlers established the town of Milan (pronounced MY-lun) in 1845, located at the center of the county, where the first courts met.

Ten years later, residents leveled an Indian mound in the middle of town to make the public square and Major John McCollough built the second courthouse, the first brick structure in Milan, on this site during 1857–1858.

[7] (This courthouse was destroyed by fire in 1908 and it was not until 1938 that it was replaced by the three-story limestone building that stands today.

[8]) The last United States General Land Office established in Missouri also operated from the square from 1849 to 1859.

Other towns platted in the county's early years included Greencastle (1857), Newtown (1858), Pollock (1873), Boynton and Cora (1877), Green City and Winigan (1880), Humphreys and Reger (1881), Osgood (1886), and Harris (1887).

The Chicago, Milwaukee & St. Paul Railway soon built a north–south line along Medicine Creek the length of the western edge of the county that served the towns of Newtown and Harris, which continues to be active today.

The county primarily remains rural agricultural land today, planted in corn and grains with family operated poultry, livestock, and dairy farms.

The highest point in the county, about 1,060 feet (320 m) above sea level, is on the primary divide between the Chariton River and Grand River drainage basins along its northern border shared with Putnam County northwest of Green City.

Senator Hillary Clinton (D-New York) received more votes, a total of 506, than any candidate from either party in Sullivan County during the 2008 presidential primary.