Smith was an active contributor to Astounding Science Fiction during the Golden Age of Science Fiction in the 1940s. His collaboration with the magazine's editor, John W. Campbell, Jr. was interrupted when Campbell's first wife, Doña, left him in 1949 and married Smith.

Smith continued regularly publishing science fiction novels and stories until 1960. His output greatly diminished in the 1960s and 1970s when he had a job that required his undivided attention. He was given the First Fandom Hall of Fame award in 1980.

He was a member of the all-male literary banqueting club the Trap Door Spiders, which served as the basis of Isaac Asimov's fictional group of mystery solvers the Black Widowers.

Smith wrote mainly about outer space, with such works as Operation Interstellar (1950), Lost in Space (1959), and Troubled Star (1957).

He is remembered chiefly for his Venus Equilateral series of short stories about a communications station in outer space. The stories were collected in Venus Equilateral (1947), which was later expanded as The Complete Venus Equilateral (1976).

His novel The Fourth "R" (1959) - re-published as The Brain Machine (1968) - was a digression from his focus on outer space, and provides one of the more interesting examinations of a child prodigy in science fiction.