While Frank Maryl Setzler was an undergraduate student at Ohio State University during the mid-1920s, he served as an assistant field director at the Ohio State Museum and worked under Henry C. Shetrone in excavations of the Hopewell and Seip mounds in central Ohio. He was later a graduate student of anthropology at the University of Chicago and took courses from Fay-Cooper Cole, Robert Redfield, and Edward Sapir. At the same time, he worked as an Indiana state archaeologist and carried out excavations of mounds in southeastern Indiana and a survey of the Whitewater River Valley. He also worked on the University of Chicago's pictorial survey of Mississippi Valley archeology.
In 1930, Setzler was appointed assistant curator in the Division of Archeology of the United States National Museum. In 1935, he was made acting head curator for the Department of Anthropology and two years later became head curator. A number of significant developments took place during his career at the Smithsonian. During the 1930s and early 1940s, the government was involved in many archaeological projects through its work relief programs, including the Federal Emergency Relief, Civil Works, Public Works, and Work Projects administrations.
Setzler not only took advantage of the assistance provided by these programs for his own archeological work, but he also participated in the CWA as Smithsonian Institution liaison officer responsible for the direction of eleven projects in the southeastern states and California. For the WPA, he served as a consultant, reviewing project proposals. While he was head curator, he participated in a study of visitor reactions to the United States National Museum exhibits and supervised the modernization of exhibits of the Department of Anthropology.
He also worked toward the removal of nonanthropological sections which had long been part of the department, expansion of the curatorial staff to include specialists outside North America, and establishment of a docent service. In addition, he was responsible for the department's efforts made necessary by World War II, including the protection of the collections, special tours for soldiers, special exhibits, and work for the Ethnogeographic Board.
Setzler was involved in surveys and excavations in southwestern Texas in an attempt to find links between Mexican Indian cultures and those of the Mississippi Valley. Related work was later carried out under Setzler's direction by museum collaborator Walter W. Taylor, who undertook archaeological work in the state of Coahuila in Mexico. Setzler also worked at sites in Chaco Canyon, New Mexico, and carried out reconnaissance along the Yampa and Green Rivers in Colorado and Utah. In 1948, he was deputy leader for the Australian-American Arnhem Land Expedition sponsored by the Smithsonian, National Geographic Society, and the government of Australia.
Setzler's chief interest, however, continued in the archaeology of the midewestern states and he developed a strong interest in the southeastern states. Included in his activities was work at Marksville, Louisiana; Proctorville, Ohio; Cumberland Island, Florida; the Kinaid site, Illinois; Cambridge, Maryland; New Martinsville, West Virginia; and Saltsville, Virginia. With John Reed Swanton, he also investigated sites of villages reported by the chroniclers of Hernando de Soto. Late in his career, he also joined C. Malcolm Watkins and Oscar H. Darter in excavating historical sites at Marlborough Town and near Bell Plains in Virginia.
Setzler was also active with a number of scientific and government organizations. He was a member of the Advisory Board for National Parks, Historic Sites, Buildings, and Monuments of the National Park Service and its secretary in 1940-1942. He represented anthropology on the National Research Council in 1940-1942 and was vice chairman of the Division of Anthropology and Psychology of the National Academy of Science in 1942-1943. In 1937-1940, he was secretary of the American Anthropological Association; and, between 1939 and 1953, he held offices with the Washington Academy of Sciences, including the presidency in 1953. He was secretary of the Anthropological Society of Washington in 1932-1937 and president in 1940-1942. In 1930-1941, he was on the council of the Society for American Archaeology.