Very early cultures living in what is now Oklahoma included the Clovis, Folsom, and Caddo Mississippian. Among the Native American tribes originally living in the area were the Apache, Arapaho, Caddo, Comanche, Kiowa, Osage, Quapaw, Tawakony, Waco, and Wichita.

The first Europeans known to visit the area were the Spaniards Hernando de Soto and Francisco Coronado, who rolled through in 1540 and 1541, respectively, searching for the "Lost Cities of Gold." The Frenchman René-Robert Cavelier, Sieur de La Salle in 1682 claimed a wide swathe of land for France; this was the Louisiana Territory, which contained all of Oklahoma except the panhandle. Spain took over the land after the French and Indian War, France retook control in 1800, and the land became American territory after the Louisiana Purchase in 1803. American explorers of the area included Lewis and Clark and Zebulon Pike, in 1804.

Oklahoma became part of Arkansas Territory in 1819. The Mexican Cession, after the Mexican-American War, included Oklahoma's panhandle, which had briefly been part of the Republic of Texas.

Congress passed the Indian Removal Act in 1830. This law required Native Americans in the southeastern part of the country to leave their ancestral homes. Oklahoma, beginning in 1834, was known as Indian Territory and was the designated new home for these tribes. One of the most famous of these journeys was the Trail of Tears. Other tribes who were the victims of forced relocation were the Cayuga, Cheyenne, Chickasaw, Choctaw, Creek, Delaware, Fox, Iowa, Kaw, Kickapoo, Miami, Modoc, Otoe, Ottawa, Pawnee, Ponca, Potawatomi, Sauk, Seneca, Shawnee, Wyandotte and Yuchi.

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