Blish was born at East Orange, New Jersey. In the late 1930s to the early 1940s, Blish was a member of the Futurians.
Blish trained as a biologist at Rutgers and Columbia University, and spent 1942–1944 as a medical technician in the United States Army. After the war he became the science editor for the Pfizer pharmaceutical company. His first published story appeared in 1940, and his writing career progressed until he gave up his job to become a professional writer.
He is credited with coining the term gas giant, in the story “Solar Plexus” as it appeared in the anthology Beyond Human Ken, edited by Judith Merril. (The story was originally published in 1941, but that version did not contain the term; Blish apparently added it in a rewrite done for the anthology, which was first published in 1952.)
Blish was married to the literary agent Virginia Kidd from 1947 to 1963.
Among his best-known works are A Case of Conscience (1958), a dramatized debate about the theological status of an alien race; Cities in Flight (1970), a collection of four earlier works in which Earth cities like New York literally take off and orbit the planet; The Seedling Stars (1957), a collection of short stories; Doctor Mirabilis (1964), a fictional study of Roger Bacon; and Black Easter; Or, Faust Aleph-Null (1968), a discussion on the death of God.
From 1962 to 1968, he worked for the Tobacco Institute.
Between 1967 and his death from lung cancer in 1975, Blish wrote authorized short story collections based upon the 1960s TV series Star Trek. He wrote 11 volumes adapting episodes of the series. He died midway through writing Star Trek 12; his second wife, J. A. (Judith Ann) Lawrence, completed the book, and later completed the adaptations in the volume Mudd’s Angels. In 1970 he wrote Spock Must Die!, the first original novel for adult readers based upon the series. (Since then hundreds more have been published.)
Blish lived in Milford, Pennsylvania at Arrowhead until the mid-1960s. In 1968, Blish emigrated to England, and lived in Oxford until his death at Henley-on-Thames, in 1975. He is buried in Holywell Cemetery, Oxford, near the grave of Kenneth Grahame.