Both the county and its county seat are named for the Cherokee Indian tribe. The word "cherokee" comes from the Chickasaw word "chiluk-ki," which means "cave people."

The county was established in 1851 and originated in 1857.  The first settlement was Cherokee, later known as Old Cherokee. In February 1857 the settlement was attacked by a tribe of Sioux Indians. After three days the band of Indians left the area and headed for the lakes region. After the citizens heard of the Spirit Lake massacre, many deserted the town.

In 1861 three men were chosen to select a suitable county seat site. Cherokee was selected, and a tax levy was used to construct the first courthouse. The 30-square-foot building was constructed of native lumber at a cost of $1,900. When the building was completed in 1864, it was used as a courthouse, public gathering place and a school.

In March of 1870 the Dubuque and Sioux City Railroad came through the county. In the fall of 1871 the voters approved the relocation of the county seat to the railroad, or New Cherokee. The following winter a committee was selected to move and repair the county court house.

A new county building was needed as early as 1880, but it was not until 1890 that voters finally approved the construction of a new courthouse. The large Romanesque-style courthouse was completed in 1892 at a cost of approximately $40,000. The pressed brick, granite and slate building was situated high on a hill overlooking the business section of Cherokee.

Approval for the construction of the present courthouse came in a November 3, 1964 election. Voters approved a $575,000 bond issue to construct the split-level, modern-looking building. The new courthouse was dedicated on October 16, 1966.