At the age of twenty, after having completed his education, he was appointed as Indian agent to the western Cherokee and sent to Arkansas. He served as an adjutant in a Cherokee regiment during the War of 1812 and participated in fighting at the Battle of Horseshoe Bend against the British-allied Creek tribe.
Ross relocated to Georgia and was chosen as a member of the Cherokee national council in 1817, becoming its president two years later and serving in that capacity for seven years. After this he became assistant chief of the eastern Cherokee, becoming principle chief the following year and serving as such until 1839, participating in the drafting of the Cherokee constitution in 1827.
During his tenure as chief he opposed displacement of the tribe from its native lands, but eventually this resistance proved futile in 1838, when President Martin van Buren ordered the removal of the tribe to present-day Oklahoma, to be enforced by Gen. Winfield Scott in what was to become known as the "Trail of Tears."
In 1839 he helped draft a constitution for the entire Cherokee nation, now located in Indian Territory, and was chosen as chief of the nation. He would remain chief until his death.