In cinema, Perelman is noted for co-writing scripts for the Marx Brothers films Horse Feathers and Monkey Business and for the Academy Award-winning screenplay Around the World in Eighty Days.

With Ogden Nash he wrote the book for the musical One Touch of Venus (music by Kurt Weill, lyrics by Nash), which opened on Broadway in 1943 and ran for more than 500 performances. His play The Beauty Part (1962), which starred Bert Lahr in multiple roles, fared less well, its short run attributed at least in part to an accompanying 11-week newspaper strike.

Perelman's work is difficult to characterize. He wrote many brief, humorous descriptions of his travels for various magazines, and of his travails on his Pennsylvania farm, all of which were collected into books. (A few were illustrated by caricaturist Al Hirschfeld, who accompanied Perelman on the round-the-world trip recounted in Westward Ha!) He also wrote numerous brief sketches for The New Yorker in a style that was unique to him. They were infused with a sense of ridicule, irony, and wryness and frequently used his own misadventures as their theme. Perelman chose to describe these pieces as feuilletons - a French literary term meaning "little leaves" - and he defined himself as a feuilletonist. Perelman's only attempt at a conventional novel (Dawn Ginsbergh's Revenge) was unsuccessful, and throughout his life he was resentful that authors who wrote in the full-length form of novels received more literary respect (and financial success) than short-form authors like himself, although he openly admired his British rival, P.G. Wodehouse.

The tone of Perelman's feuilletons, however, was very different from those sketches of the inept "little man" struggling to cope with life that James Thurber and other New Yorker writers of the era frequently produced. Although frequently fictional, very few of Perelman's sketches were precisely short stories.

Sometimes he would glean an apparently off-hand phrase from a newspaper article or magazine advertisement and then write a brief, satiric play or sketch inspired by that phrase. A typical example is his 1950s work, "No Starch in the Dhoti, S'il Vous Plait." Beginning with an off-hand phrase in a New York Times Magazine article ("...the late Pandit Motilal Nehru -- who sent his laundry to Paris -- the young Jawaharlal's British nurse etc. etc....), Perelman composes a series of imaginary letters that might have been exchanged in 1903 between an angry Pandit Nehru in India and a sly Parisian laundryman about the condition of his laundered underwear.

Perelman also occasionally used a form of word play that was, apparently, unique with him. He would take a common word or phrase and change its meaning completely within the context of what he was writing, generally in the direction of the ridiculous. In Westward Ha!, for instance, he writes: "The homeward-bound Americans were as merry as grigs (the Southern Railway had considerately furnished a box of grigs for purposes of comparison) ... ". Another classic Perelman pun is "I've got Bright's Disease and he's got mine".

He also wrote a notable series of sketches called Cloudland Revisited in which he gives acid (and disillusioned) descriptions of recent viewings of movies (and recent re-readings of novels) which had enthralled him as a youth in 1919 Providence, Rhode Island.

A number of his works were set in Hollywood and in various places around the world. He stated that as a young man he was heavily influenced by James Joyce, particularly his wordplay, obscure words and references, metaphors, irony, parody, paradox, symbols, free associations, non-sequiturs, and sense of the ridiculous. All these elements infused Perelman's own writings but his own style was precise, clear, and the very opposite of Joycean stream of consciousness. Perelman drily admitted to having been such a Ring Lardner thief he should have been arrested.Woody Allen has in turn admitted to being influenced by Perelman and recently has written what can only be called tributes, in very much the same style. The two once happened to have dinner at the same restaurant, and when the elder humorist sent his compliments, the younger comedian mistook it for a joke. Authors that admired Perelman's ingenious style included T.S. Eliot and W. Somerset Maugham.

Perelman was indirectly responsible for the success of Joseph Heller's novel Catch-22. When first published, this novel received lukewarm reviews and indifferent sales. A few months later, Perelman was interviewed for a national publication. The interviewer asked Perelman if he had read anything funny lately. Perelman - a man not noted for generosity with his praise - went to considerable lengths to commend Catch-22. After the interview was published, sales of Heller's novel skyrocketed.

Like most comic writers', Perelman's was not a happy life; his marriage to Laura West was strained from the start because of his interminable affairs (notably with Leila Hadley), and Perelman was not much of a father. He generally regarded children as a nuisance, and his son Adam ended up in a Reformatory for Wayward Boys. The two things that brought him happiness were his MG car and a tropical bird, which he pampered like babies. His Anglophilia turned rather sour when he actually had to socialise with the English themselves. Perhaps he never really recovered from the blow Fate dealt to his close friendship with Nathanael West, when the latter was killed in a car crash. Both men came from Jewish-Russian immigrant families, and their virtuoso writing style is all the more remarkable for the fact that their parents spoke Yiddish and German when they arrived in the USA.

Perelman picked up plenty of juicy expressions and liberally sprinkled his prose with these phrases, thus paving the way for the likes of Philip Roth. Both his surprisingly lacklustre biography by Herrmann and the Selected Letters ("Don't Tread On Me", edited by Prudence Crowther) suffer from the fact that "Lotharian Sid's" erotic escapades and fantasies have been censored beyond recognition to protect certain individuals.

The British expert on comic writing, Frank Muir, lauded Perelman as the best American comic author of all time in his Oxford collection of humorous prose. Now that American humorists such as Keillor have reverted to the frugal Hemingway style, it is encouraging that Perelman's exuberant verbal wit lives on in the hyperventilating prose of the British author Martin Amis.