During the American Civil War (1861-1865), after great internal conflict, the tribe sided with the Confederacy; where Stand Watie became a Confederate general.

Other Cherokees in western North Carolina served as part of Thomas' Legion, a unit of approximately 1,100 men of both Cherokee and white origin, fighting primarily in Virginia, where their battle record was outstanding. Thomas' Legion was the last Confederate unit to surrender in North Carolina, at Waynesville on May 9, 1865.

A postwar treaty with the United States freed the black slaves belonging to tribal members in Indian Territory. Under the General Allotment Act of 1887, uncompromisingly resisted by the Cherokee, plots of tribal land were forcibly allotted to individual members. Surplus lands not assigned to Cherokee individuals were parceled out by the federal government, and in 1891 the tribe’s western land extension, the Cherokee Strip or Cherokee Outlet, was sold to the United States; in 1893 it was opened, mostly to non-Indian settlers, in a famous land run. The Cherokee government was dissolved, and its people became U.S. citizens when Oklahoma achieved statehood in 1907. In this action, the Oklahoma Cherokees lost their right to elect their own chiefs who were from there on appointed by the Presidents until 1970 when the Cherokees regained their right to elect their own government via a Congressional Act signed by President Nixon. W. W. Keeler was the first elected chief of the Oklahoma Cherokees. Keeler, who was also the President of Phillips Petroleum, was succeeded by Ross Swimmer, Wilma Mankiller, Joe Byrd and Chad Smith who is currently the chief of the Oklahoma Cherokees.

Federally recognized tribal headquarters of the Keetowah Band of Cherokee are in Tahlequah, Oklahoma , while the Eastern Band of Cherokees are headquartered at Cherokee, North Carolina. State-recognized Cherokee tribes have headquarters in Georgia and Alabama. Other groups of Cherokee organizations are located in Arkansas, Missouri, Tennessee, and other locations in the United States.

They remain one of the largest tribes in the United States, and many Americans of all backgrounds claim Cherokee ancestry.

The old ways, including traditional crafts, are most strongly preserved by the Eastern Band, some of whom continue to live on the Qualla Reservation in North Carolina. The quality of North Carolina Cherokee basketry is considered to be equal to or better than that of earlier times. Farming, forestry, factory work, and are sources of income for eastern Cherokee.