Wetmore came to the Smithsonian in 1924 as Superintendent of the National Zoological Park after a fourteen-year career with the Bureau of Biological Survey (now U. S. Fish and Wildlife Service). In 1925, he was appointed Assistant Secretary of the Smithsonian in charge of the United States National Museum, a post he held until his appointment as Secretary in 1945. Wetmore retired in 1952 and was made an honorary Research Associate of the Smithsonian, where he continued his study of recent and fossil birds.
Wetmore, considered the dean of American ornithologists, also worked extensively in the field of avian paleontology and as a systematics specialist. His bibliography contained over 700 entries; he described 189 species and subspecies of birds new to science; and he made enormous natural history collections for the Smithsonian. Wetmore was a member of the American Ornithologists' Union (AOU) for seventy years, and countless professional organizations, scientific committees, and conservation groups as well. He was awarded the AOU's Brewster Medal in 1959, and its Elliott Coues Award in 1972. The National Geographic Society conferred its Hubbard Medal on Wetmore in 1957, during his forty-year association as a trustee
Wetmore was a tireless field worker, beginning as a field naturalist with the Biological Survey and continuing through the latter years of his life. He studied and collected in all regions of the continental United States, the Hawaiian Islands, and Alaska, but most extensively in the American Tropics. Wetmore surveyed the avifauna of Puerto Rico in 1911, and he spent 1920-1921 in South America studying bird migration between the continents. In the mid-1940s, Wetmore began a research program that would occupy his energies for the remainder of his life. Between 1946 and 1966 he took annual trips to Panama; making an exhaustive survey of the birds of the isthmus. This work culminated in the publication of his four volume magnum opus, The Birds of Panama.