The American Civil War disrupted the Cherokees' peace and forced on Ross and his tribe an onerous decision. Although the Cherokees had sympathies with the slaveholding South, Ross felt that existing treaties necessitated loyalty to the Union. Again, the force of circumstances and a possible cleavage within the tribe placed Ross in a difficult situation. His tribesmen were divided over the question of slavery, and although Ross was a slave owner, he had the support of the nonslaveholding majority. When Confederate agents such as Albert Pike of Arkansas pressed for a decision, Ross reluctantly counseled his people to join the secession movement, and as chief he signed a treaty with the South. Ross would later declare to Union officials that he had made the decision under duress. Indeed, at the first opportunity he fled north with his family and remained in Washington, D.C., for the remainder of the war. There he tried to convince the federal officials to reoccupy Indian Territory and accept the coercive nature of the Cherokees' defection.
At the end of the war Ross again faced formidable odds and the likelihood of a Cherokee division. His wartime opponents insisted that Ross was a rebel at heart and should be divested of his office. They also wanted the tribe split along party lines based on Union loyalty or affiliation with the Confederate cause. Ross resisted the disintegration of his people and worked to obtain a treaty securing permanent land rights for the Cherokees.