Colusa County was one of the first counties of California, created in 1850 at the time of statehood. Parts of the county's territory were given to Tehama County in 1856 and to Glenn County in 1891.

The county was named after two Mexican land grants; Coluses (1844) and Colus (1845). The name of the county in the original state legislative act was spelled Colusi, and often in newspapers was spelled Coluse. The word is derived from the name of a Native American tribe living on the west side of the Sacramento River.

The meaning of the word calaveras is "skulls." This county takes its name from the Calaveras River which was reportedly so designated by Spanish explorer Gabriel Moraga when he found, on the banks of the stream, many skulls of Native Americans who had either died of famine or had been killed in tribal conflicts over hunting and fishing grounds.