Before college, he was first homeschooled by his mother, and then spent the final two years in boarding school.

He was the first resident lecturer at the Johns Hopkins School of Hygiene and Public Health and was later professor of epidemiology.

His work included studies of the epidemiology of poliomyelitis, influenza, diphtheria, and tuberculosis.

In 1906, Frost assisted in the first successful arrest of a yellow fever epidemic in the United States.

He also helped field investigations regarding typhoid outbreaks and water pollution by applying his knowledge of microbiology laboratory techniques.