He resigned from his third term as governor to accept appointment by President James Monroe as the U.S. agent to the Creek Indians. One of Mitchell's responsibilities was the negotiation of the Treaty of the Creek Agency (1818), by which the Creek ceded land to the United States. He was accused in the American Importation Case of 1820 of smuggling slaves into Creek and US territory, in violation of the 1808 law against the American slave trade. While his direct responsibility remains controversial, Mitchell allowed those engaged in this illegal activity to seek refuge for their captives at the agency he supervised along the Flint River. The incident resulted in a major inquiry and his dismissal by President James Monroe in 1821.