His classic science fiction novel What Mad Universe (1949) is a parody of pulp SF story conventions. The novel functions both as a critique of its genre and a superior example of it. It may have provided a model for Philip K. Dick when he later created his own stories set in alternate personal realities. Martians, Go Home (1955) is both a broad farce and a satire on human frailties as seen through the eyes of a billion jeering, invulnerable Martians who arrive not to conquer the world but to drive it crazy.

The Lights in the Sky Are Stars (1952) tells the story of an aging astronaut who is trying to get his beloved space program back on track after Congress has cut off the funds for it.

One of his most famous short stories, "Arena", was used as the basis for the episode of the same name in the original series of Star Trek. It was also the basis of a 1964 episode entitled "Fun and Games" of The Outer Limits, probably the 1999 episode "The Rules of Luton", and possibly the Blake's 7 episode "Duel".

Brown's first mystery novel, The Fabulous Clipjoint, won the Edgar Award for outstanding first mystery novel. It began a series starring Ed and Ambrose Hunter, and is a depiction of how a young man gradually ripens into a detective under the tutelage of his uncle, an ex—private eye now working as a carnival barker.

The books make use of the threat of the supernatural or occult before the "straight" explanation at the end. Night of the Jabberwock is a bizarre and humorous narrative of an extraordinary day in the life of a small-town newspaper editor.

Also highly regarded are The Screaming Mimi (which became a 1958 movie starring Anita Ekberg and Gypsy Rose Lee, and directed by Gerd Oswald, who also directed the "Fun and Games" episode of The Outer Limits) and The Far Cry, powerful noir suspense novels reminiscent of the work of Cornell Woolrich, and The Lenient Beast, with its experiments in multiple first-person viewpoints, among them a gentle, deeply religious serial killer, and its unusual (for a book written in the 1950s) examination of racial tensions between whites and Latinos in Arizona.

Even more experimental was Here Comes a Candle, which is told in straight narrative sections alternating with a radio script, a screenplay, a sportscast, a teleplay, a stage play, and a newspaper article.

He wrote several short stories about Satan and his activities in Hell.

Many of his science fiction stories were shorter than 1,000 words, or even 500 words.

The depiction of aliens who are completely alien mentally as well as physically and are completely bent on humanity's destruction is similar to that of the Arctuarians in Brown's earlier What Mad Universe.

His short story "Arena" was voted by Science Fiction Writers of America as one of the top 20 SF stories ever written before 1965. His short story "The Waveries" was described by Philip K. Dick as "what may be the most significant...startlingly so...story SF has yet produced." "Knock" is well known for its opening, which is a complete two-sentence short short story in itself.

Ayn Rand singled out Brown for high praise in her book The Romantic Manifesto. The famous pulp writer Mickey Spillane called Brown "my favorite writer of all time". Science fiction and fantasy writer Neil Gaiman has also expressed fondness for Brown's work, having his novel Here Comes A Candle being read by the character Rose Walker in the collection The Kindly Ones of The Sandman.

Brown also had the honor of being one of three dedicatees of Robert A. Heinlein's Stranger in a Strange Land.