Pulp editor Mort Weisinger (for whom he created Captain Future), offered him his first job in comics, and he became one of the regular contributors to Superman. He wrote the first ever Batman and Superman team-up in Superman #76, which inspired editor Jack Schiff to create a regular title (World's Finest) of Batman/Superman team-ups, the majority written by Hamilton.

Edmond Hamilton is co-credited (along with e.e. 'Doc' Smith) as the founder of the Space Opera genre of science fiction. His novel City at the World's End inspired Robert Heinlein's novel Farnham's Freehold, as well as an episode of the TV series Doctor Who, and he adapted it to comics as the famous story, "Superman Under the Red Sun", which appeared in Action Comics #300.

He retired from comics in 1966. Hamilton was married to also writer and screenwriter Leigh Brackett.