5 Feb. 1805–10 May 1893
During this time Thomas became a good friend of Yonaguska, the principal chief of the Cherokee who chose to remain under white rule following the land cession and treaty of 1819. As a result of this friendship, the young white man was adopted into the Cherokee tribe and given the name Wil-Usdi (Little Will) because of his small size. He not only continued his businesses, but he also began to read law and act as the attorney for the North Carolina Cherokee. Thomas's first major action on their behalf was to draw up a simple plan of government that allowed them to coordinate their responses to government policies.
The relationship between the federal government and the Cherokee reached a critical stage after the signing of the Treaty of New Echota, which provided that all members of the Cherokee nation must move to the West. The North Carolina Cherokee maintained that they were exempted from the removal order and contracted with Thomas to represent them in Washington. The assignment lasted from 1836 to 1848, and Thomas often spent months at a time in Washington. Despite his commitment to the Cherokee cause, he openly speculated in lands made available for sale by the Cherokee removal. He also aided the U.S. Army in its efforts to locate Cherokee from other states who hid in North Carolina to escape removal. These contradictory actions, ironically, served to strengthen his position with the Cherokee, local whites, and the federal government.

His assistance to the Cherokee and his large landholdings made Thomas an influential figure in western North Carolina. He entered politics and served continuously in the North Carolina state senate from 1849 to 1861. A Democrat, Thomas was an active member of the Committee on Internal Improvements and served as chairman for four terms. He consistently sponsored or supported legislation to improve the transportation system of the western portion of the state including such projects as plank roads and the Western North Carolina Railroad. These same years were a time of change in his personal life. He increasingly neglected his business interests and became "land poor" and deeply in debt; in 1857, at age fifty-two, he married Sarah Jane Burney Love, the daughter of a wealthy Haywood County man. Their three children—William H., Jr. (b. 1858), James R. (b. 1860), and Sarah L. (b. 1862)—soon gave him even greater personal responsibilities.
The Civil War added new challenges to Thomas's life. He was an ardent Southern patriot and voted for secession at the state convention in May 1861. After returning home, he persuaded the Cherokee to support the Confederacy and organized a home guard group. In April 1862 he joined the Confederate army and was named captain of a company that included many Cherokee. That September the company took part in a skirmish at Baptist Gap in eastern Tennessee, which ended with some Cherokee scalping wounded Union soldiers. Thomas was soon promoted to colonel and placed in command of the Sixty-ninth North Carolina Regiment with several companies of Cherokee in the unit. This force, known as Thomas's Legion, served as the major line of defense between the Federal presence in eastern Tennessee and Confederate North Carolina. Thomas was one of the last Confederates to surrender, along with General James G. Martin, in Waynesville on 10 May 1865.
His career after the war was one of increasing personal and financial difficulties. The demands of the conflict led to a physical and emotional collapse. In March 1867 Thomas was a person with a mental illness and confined to the state psychiatric hospital in Raleigh. His businesses failed and creditors began to dismantle his empire; for example, the sheriff of Cherokee County sold off more than 115,000 acres of Thomas's land in 1869 alone. Even the Cherokee had to go to court to secure control of their land from his creditors. Thomas still experienced periods of mental stability and related many of the Cherokee myths to researcher James Mooney. He died in the state mental hospital in Morganton and was buried in the public cemetery in Waynesville. Thomas was the one individual most responsible for the creation of the Eastern Band of the Cherokee and a consistent champion of the economic development of the mountain region of North Carolina.