When he was twently-one years old, Mooney wrote to the U.S. Bureau of American Ethnology, asking to be hired to map the North American tribes. He was turned down. Finally, in 1885, he went to Washington, D.C., for a face-to-face meeting with the head of the bureau. He was then offered a job as an assistant.

While in Washington, Mooney met Cherokee Chief Nimrod Jarrett Smith, who gave him much linguistic and cultural insight into the Eastern Band. At Chief Smith’s invitation, Mooney made his first trip to Western North Carolina in 1887 to observe the Cherokee Green Corn Dance, a ritual not performed again by the Eastern Band of Cherokee for over a century. He identified three Cherokee dialects, collected many artifacts, and established friendships and trust within the tribe.

Mooney could not have chosen a better time to study the Cherokee. The 1880s brought great changes for the Eastern Band, many for the worse. Railroads were being built in the area, schools were forcing indoctrination of white culture, and intermarriage was becoming increasingly common. As a result, the traditional Cherokee medical arts were dying out in favor of white medicine, and many rituals were falling into obscurity.

Mooney wanted to record these dying rituals, so he sought out such people as Swimmer and John Ax, who were familiar with the old practices and knew tribal history. Through Swimmer, Mooney acquired a valuable manuscript filled with rituals and practices. He used this manuscript, along with other information he had collected, to write the Bureau of Ethnology Report that would become Sacred Formulas of the Cherokees, published in 1891.

James Mooney headed west in the 1890s to spend time with the Cherokee in Oklahoma and the Great Plains, where he studied the notable Ghost Dance. In 1898, he began to put together the research notes and material for his next work. He returned to Western North Carolina to check the final details, and in 1901, Myths of the Cherokee was published as another Bureau of Ethnology Report.

In 1911, Mooney continued his work on the six hundred or so sacred formulas that he had acquired in written form, primarily from Swimmer. Despite his failing health, he traveled in June to Big Cove, North Carolina, to have Cherokee shaman Will West Long help him with his translations and transliterations. In addition to his linguistic help, Long provided additional formulas which Mooney had never seen.

Mooney returned to Big Cove in July of 1913. During this visit he was asked to join in a "going to water" rite, a great privilege indicating his acceptance by the tribe. Despite his worsening health, he revisited Big Cove during the summers of 1914 through 1916. His travels came to a halt two years later, however, when the Commissioner of Indian Affairs punished him for his support of Indians’ rights to use peyote as a religious sacrament. As a result, he finished his career at a desk in Washington.

James Mooney died in December of 1921. His writings on the practices and rituals of the Cherokee are still considered to be the authoritative reference, although he always intended to write a more definitive work on the subject.