Nathans went to public schools and then to the University of Delaware, where he received his BS degree in chemistry in 1950. He received his MD degree from Washington University in St. Louis in 1954. After earning his MD degree, Nathans went to the Columbia-Presbyterian Medical Center for a one-year medical internship with Robert Loeb.

Nathans returned to Columbia Presbyterian for a two-year residency in 1957, again on Robert Loeb's Service. He continued working on the Problem of protein synthesis as time allowed. In 1959, he decided to work on the research full time and became a research associate at Fritz Lipmann's lab at the Rockefeller Institute in New York.

In 1962, Nathans came to Johns Hopkins University School of Medicine as an assistant professor of microbiology. He was promoted to associate professor in 1965 and to professor in 1967. He became the Director of the microbiology department in 1972 and served in that position until 1982. In 1981, the department of microbiology was renamed the department of molecular biology and genetics.

In 1982 Johns Hopkins University made Nathans a University Professor, a position in which he served until his death in 1999. He also became a senior investigator of the Howard Hughes Medical Institute unit at the School of Medicine in 1982.

From 1995-1996 Nathans served as the interim President of Johns Hopkins University.

In January 1999, Johns Hopkins University established the McKusick-Nathans Institute of Genetic Medicine, a multidisciplinary clinical and research center named for Nathans and pioneering medical Geneticist Victor McKusick. Nathans was also given six honorary doctorates over the span of his career.