Access into the region at first was difficult, which discouraged settlement. The first effort to develop routes into the area was in 1862 when a supply train with cattle crossed the Scott Trail. This was also the first group of non-natives to spend the winter in central Oregon. The discovery and development of the Santiam Pass in the 1860s improved access into the area.

Crook County was formed from the southern part of Wasco County on October 24, 1882, and established Prineville as the county seat. The voters confirmed the choice of Prineville, the only incorporated town in the county, in the 1884 general election.

The county was named after Major-General George Crook from Ohio, who served in the American Civil War and afterwards fought in the Indian Wars. As of 2000, the population is 19,182.