Educated in the county school, there, Wiley soon rose to local prominence and was appointed by the legislature to be commissioner of the Elbert County academy in 1808.
He served in the War of 1812, was elected in 1817 major-general of the 4th Division of Georgia militia, and resigned in 1824. In 1819 he served on a commission to determine the boundary line between Georgia and East Florida (Gov. William Rabun to Secretary of War, February 19, 1819, Georgia Department of Archives and History, Atlanta). He was a member of the state Senate from 1817 to 1819, when he resigned. He served in the federal House of Representatives from 1821 to 1833. As chairman of the committee of military affairs he obtained payment of Georgia militia claims of 1793 and 1824.
A bitter opponent of protection, he expressed the view that the South would "be driven to the necessity of resistance" and, while he loved the Union, that "he 'would go with him who goes the farthest' in an effort to stave off oppression". In close accord with Jackson on Indian removal, he was appointed as agent of the Seminole Indians in Florida. Instructed to superintend the removal of the Indians on the Apalachicola and Chattahoochee rivers under the treaties of Payne's Landing of 1832, and Fort Gibson of 1833, he won the friendship of some of the chiefs and in 1834 led John Blount and Davy Elliott, with their bands, to New Orleans, where he paid them $8, 000 of their allowance in cash. This action was approved by Elbert Herring, then commissioner of Indian affairs. In council after his return, he found some of the chiefs unwilling to emigrate. He made clear Jackson's determination that they go, but Osceola led a group that threatened resistance. Thompson then ordered the sale of liquor and ammunition to the Indians and the purchase of their slaves stopped, and he asked for troops to aid in removal. Jackson approved the order forbidding trade and ordered Gen. Duncan L. Clinch with troops to Florida.
On July 8, 1834, Thompson was appointed "superintendent of emigration" and was to continue also as Seminole agent. In a council of 1835 he agreed that the Seminole should be transported by water in one body, rather than overland in three annual parties, as the earlier treaties had provided. When Osceola was still hostile and interrupted the council, Thompson harshly rebuked him and removed him and four other disgruntled chiefs, an action that General Clinch termed as judicious handling of the difficulty. Jackson, however, forbade the removal of chiefs, believing it would arouse hostility, and the press condemned Thompson's action as high-handed and tyrannical. Osceola, still obdurate, later visited Fort King and used abusive language toward Thompson and the United States government because of the forced removal and the seizure of his young wife as a slave. Thompson warned him and then put him in chains but finally released Osceola, who pretended to be penitent and returned a few days later with seventy-nine recalcitrants who appeared to agree to emigrate. However, with a band of sixty warriors Osceola lay in wait for two days near Fort King. As Thompson and Lieut. Constantine Smith were walking, the band attacked and shot Thompson dead, and then scalped him. He was buried at Fort King but later his wife, formerly Mrs. Ellington, had his body removed to Elberton, Ga. , where it was buried on his estate.