Born of a Scottish father and a mother who was part Cherokee, the blue-eyed, fair-skinned Tsan-Usdi (Little John) grew up as an Indian, although he was educated at Kingston Academy in Tennessee. In the early 19th century he became the leader of the Cherokee resistance to the white man's acquisition of their valuable land, some 43,000 square miles (111,000 square kilometres) on which they had lived for centuries. From 1819 to 1826 Ross served as president of the National Council of Cherokees, who by this time had become a settled people with well-stocked farms, schools, and representative government. In 1823 he exposed attempts by federal commissioners to bribe him into approving Cherokee land sales.

Five years later Ross became principal chief of the Cherokee Nation, headquartered at New Echota, Ga., under a constitution that he helped draft. His defense of Cherokee freedom and property used every means short of war. In the process he was imprisoned for a time and his home confiscated. His petitions to President Andrew Jackson, under whom he had fought during the Creek War (1813–14), went unheeded, and in May 1830 the Indian Removal Act forced the tribes, under military duress, to exchange their traditional lands for unknown western prairie.

In 1838–39 Ross had no choice but to lead his people to their new home west of the Mississippi River on the journey that came to be known as the infamous “Trail of Tears.” In the West Ross helped write a constitution (1839) for the United Cherokee Nation. He was chosen chief of the new government, an office he held for the remainder of his life.