The son of a dairy farmer, McKusick was born in Parkman, Maine, and educated at Tufts University, Medford, Massachusetts. He went on to Johns Hopkins, Baltimore, where he qualified as an MD in 1946 and where he trained as a cardiologist. McKusick remained at Johns Hopkins and served as professor of medicine from 1960 and, from 1985, as professor of medical genetics.

The name of McKusick has become identified with a book, an encyclopedic listing of human gene loci, titled Mendelian Inheritance in Man, but more commonly referred to as MIM. In 1911 E. B. Wilson identified the first gene locus – the gene for color blindness on the X-chromosome. Over the years other genes were identified and located. By 1966, when the first edition of MIM appeared, 68 genes had been mapped on the X-chromosome. McKusick went on to describe a total number of 1487 human genes. By the eighth edition of MIM, published in 1988, improved techniques in cytogenetics allowed the identification of 4344 gene loci. Two further editions of MIM, in 1990 and 1992, continued to add to the total. A version now exists on the World Wide Web.