Sublette County encompasses mostly the upper Green River Valley and the upper Hoback River. The vast majority of area is west of the Continental Divide in what was called Oregon Country before 1849. This was jointly claimed by the United States and Great Britain from 1818 to 1846. The reality is, until buffalo were virtually wiped out and natives forced onto reservations by the 1860s and 1870s, Native Americans dominated the west and nations like the United States, Great Britain, Russia, Spain, France and Mexico just claimed parts of it.

There is more than 10,000 years of archaeological evidence of native occupation of the upper Green River Valley. It is impossible to identify any tribal affiliation through most of that time, but it is likely the Shoshone ancestors have occupied the valley for thousands of years. During the horse and buffalo culture era of the 1700s and 1800s, now collectively called Plains Indians, tribal territories shifted dramatically with much more mobile and resource-rich cultures. By the time the mountain men arrived in the early 1800s, no tribes lived in the upper Green River Valley year-round, probably because of harsh winters, but the Shoshone and Crow were the most often reported in the valley, usually on extended buffalo hunts in the summer. Many other tribes including Bannock, Ute, Blackfeet, Sioux, Arapahoe and Flathead were also coming to and through the valley.

From the time Oregon Territory was formed in 1849 and Wyoming Territory was formed in 1868, various portions of what is now Sublette County on the west side of the Continental Divide were governed by six different United States territories: Oregon, Washington, Idaho, Nebraska, Dakota and Wyoming. Small portions of what is now Sublette County on the southeast corner and northern tip located on the east side of the Continental Divide were additionally controlled by Louisiana and Missouri Territories until the other territories were formed.

From 1861 to 1921, when Sublette County was formed, the 110 west longitude line (running north and south) split control in half of the upper Green River Valley. It was originally a border between Nebraska and Washington Territory. When Wyoming Territory was formed in 1868, it was the border between Idaho and Utah Territories on the west and Dakota Territory on the east. And by 1869, it was the border between Uinta County on the west and Sweetwater County on the east.