Swadesh taught at the University of Wisconsin–Madison from 1937 to 1939, and then during World War II worked on projects with the United States Army and Office of Strategic Services.

He became a professor at the City College of New York after the war's end, but was fired in 1949 due to his membership in the Communist Party.

He was one of the pioneers of glottochronology and lexicostatistics, and is known for his creation of the Swadesh list, a compilation of basic concepts believed to present across cultures and thus suitable for cross-linguistic comparison.

Inspired by Sapir's early lists of word similarities among Native American languages, he began a life work in comparative linguistics.

In May 1939 Swadesh went to Mexico, where he had been hired to assist the government of Mexican President Lázaro Cárdenas, who was promoting the education of indigenous peoples.

His Mexican colleagues remembered him for his impressive physical complexion, nicknaming him "The Paunch", as well as for his outspoken Communism.

[1] Returning to the U.S., during the Second World War Swadesh worked on military projects for the U.S. Army and the OSS to compile reference materials on Burmese, Chinese, Russian, and Spanish.

Swadesh had been a member of the Denver Communist Party and was active in the protest movement against the execution of convicted spies, Julius and Ethel Rosenberg.

[4] Swadesh continued to work in the United States until 1954, aided by limited funding from the American Philosophical Society of Philadelphia.

He was developing plans for a major research project in Western Canada at the time of his death, in the summer of 1967.

Swadesh became a consultant with the International Auxiliary Language Association, which standardized Interlingua and presented it to the public in 1951 (Esterhill 2000).

In this role, he originated the lists of 100 and 200 basic vocabulary items, used (with some variation) in both lexicostatistics and glottochronology for comparison among languages.