The county is named in honor of the two-time governor of the state of New York, DeWitt Clinton.

The county was established in 1837.  The original county seat originated in 1840 was Camanche. However, this county seat was changed to Vandenburg (later called DeWitt) the following year by a petition to the Territorial Legislature. DeWitt was the better choice due to its location in the geographic center of the county.

The first courthouse was constructed of basswood timbers. This courthouse also doubled as a hotel, with court being held on the first floor and the attic being used as sleeping quarters for jurors and witnesses.

This courthouse was used until 1846, when it was considered to be inadequate. County business was then conducted in various locations until 1854, when the second courthouse was completed. This 40-foot x 50-foot building was to be a duplicate of the Scott County courthouse. The total cost of the building was $6,000.

The majority of Clinton County's population lived along the Mississippi River. Therefore, it was not long before there was a call to relocate the county seat closer to the population. In 1869 the town of Clinton won the right to become the county seat. An election was held, and Clinton beat out rival Lyons by 511 votes. A courthouse was then erected in only 23 days at a total cost of $3,200.

This small courthouse was replaced in 1878 by a small, fireproof brick structure. Cost of this building was $5,000. It served the county until 1897, when the present courthouse was completed. The $168,000 present courthouse is built of red sandstone and granite. It has a large central tower that is constructed of copper, which has weathered to a bright green.

On June 3, 1960, Camanche was the scene of the most tremendous tornado on record. Not a building, tree, fence, animal, or human being in the tornado's path escaped. It lasted only about three minutes, but the village of 1,200 people was almost totally destroyed. Entire buildings were pulverized, poultry had their heads completely twisted off and the feathers cleanly plucked, parts of human bodies were strewn about the wreckage, and iron wagon wheels were straightened out perfectly flat. The most reliable authorities of the time estimated the total number killed at 134.