The series was created by writers Barry Took and Marty Feldman — with other writers contributing to later series after Feldman returned to performing — and starred Kenneth Horne, with Kenneth Williams, Hugh Paddick, Betty Marsden, Bill Pertwee and Douglas Smith. It had musical interludes by the Fraser Hayes Four, and accompaniment by Edwin Braden and the Hornblowers, except for the fourth series, when the musical duties were performed by The Max Harris Group. Took and the cast had worked on the predecessor series Beyond Our Ken.

Round the Horne featured a parody a week, several catchphrases, and many memorable characters. The show often opened with a deadpan delivery by Horne of "the answers to last week's questions"; questions which listeners had neither heard nor knew about, and which were laced with (what were for BBC Radio at that time) incredible double entendres and sexual innuendo, such as:

Another type of opening featured announcements about a particular event, e.g. Coat A Sheep in Raspberry Jam Week, Immerse an Orangutan in Porridge Week, Smear A Traffic Warden in Bloater Paste For Asia Day, or something equally bizarre. This would be the excuse for all sorts of happenings, such as the two-man inter-rabbi bobsleigh championships (to be held on the down escalator at Leicester Square underground station — weather and platform tickets permitting), Formation Goat Nadgering, Paso Doble Jockey Wagging, Floodlit Horse Massage, and Nark Fettering on Ice, and reports of the latest activities of the Over-Eighties Nudist Leapfrog (or Basketball, or Judo) Team.

One of the most popular sketches was Julian and Sandy, featuring Paddick and Williams as two flamboyantly camp out-of-work actors, speaking in the gay slang Polari, with Horne as their unknowing comic foil. They usually ran fashionable enterprises in Chelsea which started with the word 'Bona', for example 'Bona Pets', or in one episode a firm of solicitors called 'Bona Law' ("We've got a criminal practice that takes up most of our time").

Fiona and Charles was a regular comedy sketch in the show. Betty Marsden played Dame Celia Molestrangler, and Hugh Paddick was 'ageing juvenile' Binkie Huckaback. Their characters — Fiona and Charles — were a pair of lovestruck, dated cinema idols engaging in stilted, extraordinarily polite dialogues, in scenes that were parodies of Noël Coward's style, most particularly that of Celia Johnson and Trevor Howard in Brief Encounter. Typical dialogue (imagine it spoken in BBC English) included:

These sketches would also feature long lists of synonyms but finishing with the opposite, such as:

Other characters included J. Peasemold Gruntfuttock (Williams), the world's dirtiest dirty old man (who wanted, above all else, to get his hands on Judith Chalmers). He was also the self-styled King (later Dictator) of Peasemoldia, a small slum area of the North of London just off the Balls Pond Road, together with his wife Buttercup (Marsden), whose catch phrase was "Hello cheeky-face!". In the 3rd series, it was reported that Gruntfuttock had died, and an entire programme was dedicated as a tribute to him. However, without explanation, the character was soon resurrected. In the same series, the Gruntfuttocks appeared as King Louis and his queen in a spoof of The Three Musketeers.

Horne's adversary in many James Bond parodies was the Oriental criminal mastermind (and Fu Manchu parody) Dr Chu N Ginsberg MA (failed) (Williams, accompanied by his common-as-muck concubine Lotus Blossom, played by a cockney Paddick) and there were parodies of popular British TV entertainers such as Eamonn Andrews ("Seamus Android", played by Pertwee), Simon Dee, Wilfred Pickles (both played by Williams), and "Daphne Whitethigh", presumably based on journalist Katharine Whitehorn and played by Marsden, a development of Fanny Haddock, her Fanny Cradock take-off from Beyond Our Ken.

The shows featured old English folk singer Rambling Syd Rumpo, played by Williams, who sang such delightful and parodic nonsense ditties as "Green Grow My Nadgers Oh!", "Song of the Bogle Clencher", and the timeless "Ballad of the Woggler's Moulie". All Rambling Syd's songs were new words set to old public domain folk melodies, such as "The Lincolnshire Poacher", "Oh My Darling, Clementine", and "Widecombe Fair". Another of Rambling Syd's immortal verses ran:-

Another regular character, who had also first appeared in Beyond Our Ken, and who appeared in the script as "Dentures", was Stanley Birkenshaw, played by Paddick and characterised as a man with ill-fitting false teeth who was utterly incapable of pronouncing the letter S without spraying saliva all over the set. He would often appear as a character in a sketch; in the 2nd series, when Horne decides he wants to be a seaside end-of-the-pier-show impresario, one of the acts he auditions is "Dentures" as 'The Great Omipaloni, the world's fastest illusionist - and also the dampest'; in the 3rd series he was Captain Ahab in the first part of The Admirable Loombucket; also in the 3rd series, in The Big Top, Luigi Omipaloni, the trapeze artist at Cuckpowder's Mammoth Circus, and Buffalo Sidney Goosecreature, the fearless desperado and adversary of The Palone Ranger; in the 4th series in Apache Story, he is Rain In The Face - Kenneth Williams, as Billy Two Cheeks, exclaims "He speaks with forked tongue!"; and in Bona Prince Charlie the appropriately named Angus McSpray - Horne remarks: "After he'd finished speaking, there wasn't a dry eye in the place - or a dry anything else for that matter." "Dentures" would often open the show in the style of a toastmaster: ("My lordsssss, ladiesssss and gentlemen," etc....). and on one occasion in the 3rd series as a wrestling tournament MC; Horne comments after being introduced as 'Your referee for the contest - Kenneth "Man Mountain" Horne': 'That was Hugh Paddick, the wrestling vicar of St Barnabas Without.'