He was born into a military family, and demonstrated an early interest in zoology by collecting local wildlife around his father's army posts.

Once in South Bend, he began to publish medical studies, too, but continued his work in mammalogy, with a particular focus on the local fauna of Indiana.

Lyon acquired the rank of major in the Medical Reserve Corps during World War I, and was appointed president of the American Society of Mammalogists from 1931 to 1932.

The first hint of the young Lyon's future scientific interests came while they were stationed at Watertown Arsenal, near Boston, Massachusetts, where he began collecting insects and animals from the local area.

[2] Upon completion of his first degree, Lyon spent a year (1897–1898) at North Carolina Medical College, where he taught bacteriology.

In conjunction with his graduate studies, he moved to Washington, D.C., in 1898 to become a part-time Aid in the Division of Mammals at the United States National Museum (USNM).

[1][2] In the latter half of 1915, Lyon began teaching at George Washington University Medical School, handling courses in bacteriology and pathology until 1917, and veterinary zoology and parasitology from 1917 until 1918.

[12] Lyon was the first to describe the Bornean white-bearded gibbon (Hylobates albibarbis),[13] the Gansu pika (Ochotona cansus),[14] the Sumatran porcupine (Hystrix sumatrae),[15] the shadowy broad-nosed bat (Platyrrhinus umbratus),[16] and two species of slow loris from Borneo, Nycticebus bancanus and Nycticebus borneanus.

[19] Until the move to Indiana, Lyon wrote many papers in mammalogy, focusing primarily on morphology, systematics, and zoogeography.

[1] In addition to his Ph.D. thesis, entitled "Treeshrews: An account of the mammalian family Tupaiidae",[20] he authored papers about other mammals of the Far East, with which he had become very familiar through his study of the collections that were sent to the USNM.

[20] Following the end of his relationship with the USNM in 1912, Lyon continued to write mammalogy material and began publishing basic medical studies.

[1] After moving to Indiana, the focus of his publications shifted primarily to medical issues and mammalogy within his new home state.

[3] Lyon and his wife attended scientific meetings together; in 1911, they traveled to Europe to see museums and to visit famous zoologists.

[28] While living in South Bend, Lyon became close friends with Reverend Julius A. Nieuwland, CSC, a botanist and chemist at the University of Notre Dame.

They went on field trips and collected plant specimens[22] that were incorporated into Lyon's second herbarium, which he made in his spare time with the help of his wife, Nieuwland, and Austrian botanist Theodor Just.