The Upper Arkansas Indian Agency was established in 1855 at Bent’s New Fort to service tribes along the upper part of the Arkansas River in eastern Colorado and western Kansas. It was also known as the Big Timbers Agency for the extensive stands of cottonwoods along the Arkansas River. In 1866 the agency moved to Kansas.

The American Indian groups served by the Upper Arkansas Agency were once under the supervision of the Upper Platte Agency, which was established near Fort Laramie, Wyoming, in 1846. But due to their nomadic nature, there were no permanent headquarters set for them. With the establishment of the Upper Arkansas Agency, members of this agency became responsible for the Southern Cheyenne and Arapaho tribes as well as the Kiowa, Comanche, Apache (Kiowa Apache), and Caddo. Eventually, a separate agency, the Kiowa Agency, was established in 1864 to serve the Kiowa, Comanche, Apache (Kiowa Apache), and Caddo, but the new agency continued to work closely with the Upper Arkansas Agency until the Native Americans were moved to Indian Territory in present-day Oklahoma.

The original agency was assigned to the Central Superintendency and was under its supervision until the establishment of the Colorado Superintendency in 1861. Between 1855 and 1861, the agents of the Upper Arkansas Agency stayed at Bent’s New Fort, including John W. Whitfield (March–December 1855), Robert C. Miller (1855–59), William W. Bent (1859–60), and Albert G. Boone (1860–61). At Fort Wise, the Cheyenne and Arapaho signed a treaty that ceded all of their land in Colorado except a small reservation in southeastern Colorado near Sand Creek. During this time, Samuel G. Colley was the agent for the Upper Arkansas Agency, and he stayed at Fort Wise. Colley was the cousin of William P. Dole, the commissioner of Indian Affairs under Abraham Lincoln’s administration. Colley had no experience with Native Americans and failed to attend or even attempt to persuade chiefs to attend a conference in 1863 with Colorado territorial governor John Evans. Consequently, Colley’s son, Dexter, followed the neglectful example of his father when he operated a nearby trading post (he was accused of selling natives the treaty goods they were supposed to receive for free).

After 1862 the agents for the Upper Arkansas Agency stayed at Fort Lyon. Construction of permanent buildings for the federal agency began but ceased due to the poor conditions of the area and the Sand Creek Massacre in 1864. The location of the administration of the Upper Arkansas Indian Agency remained uncertain because of the constant movement of Native Americans. The agency was first reassigned to the Central Superintendency in 1866 and was headquartered at Fort Zarah, Kansas, for a short time. It was then moved to Fort Larned, Kansas, until 1867, when the Medicine Lodge Treaty directed the Cheyenne and Arapaho to move to Indian Territory. It was not until 1869, however, that an executive order forced the Southern Cheyenne and Arapaho to move to the reservation, located on the North Fork of the Canadian River in Oklahoma.