Initially in his post-graduate work Malzberg sought to establish himself as a playwright as well as a prose-fiction writer. He first found commercial and critical success with publication of his surreal novelette "Final War" in The Magazine of Fantasy and Science Fiction under the name K. M. O'Donnell in 1968. In 1965, he had begun working for the Scott Meredith Literary Agency, and would intermittently continue with SMLA through the next several decades, being one of its last caretakers.
Malzberg's writing style is distinctive, with frequently long, elaborate though carefully constructed sentences and under-use of commas. Most of his science fiction books are short, present-tense narratives concerned exclusively with the consciousness of a single obsessive character. His themes, particularly in the novels Beyond Apollo (1972) and The Falling Astronauts (1971) about the US space exploration programme, include the dehumanisation effects of bureaucracy and technology; his treatment of these themes sometimes exhibits strong resemblances to Kafka, accompanied by Unreliable narrator techniques. In novels like Galaxies (1975) and Herovit's World (1973), Malzberg uses metafiction techniques to subject the heroic conventions and literary limitations of space opera to biting satire.
His editorial career has included stints at a men's-magazine publisher, and as editor of fiction magazines Amazing Stories and Fantastic in 1968, as well as anthologies such as Final Stage (with Edward L. Ferman) and several with Bill Pronzini, among others. He has been an enormously prolific writer, particularly in the early 1970s, in a variety of fields, most often in crime fiction and fantastic fiction, with notable, ambitious work published in other fields, as well, under his own name, as O'Donnell, and as Mike Barry and under other pseudonyms. He has also often written in collaboration with Pronzini, Kathe Koja, and others. He wrote the novelization of the Saul Bass-directed 1974 film Phase IV.
A devotee of classical music, he is also a violinist, and performed in the premiere performance of work by Somtow Sucharitkul; he has also been nominated several times for the Hugo Award, and won the Locus Award for his collection of historical and critical essays, The Engines of the Night (1982).
Malzberg's work has been widely praised by critics, while being attacked by proponents of hard science fiction for its pessimistic, anti-Campbellian tenor. The dystopian and metafictional elements of Malzberg's work have led to numerous parodies inside science fiction, including Paul Di Filippo, whose first published story, "Falling Expectations," was a parody of Malzberg.
For the last several years, Malzberg has collaborated with friend and fellow science fiction writer Mike Resnick on a series of more than 40 advice columns for writers in the Science Fiction and Fantasy Writers of America's quarterly magazine SFWA Bulletin.
Malzberg, a graduate of Syracuse University, has been a resident of Teaneck, New Jersey for many years.