Cleese was born in Weston-super-Mare, Somerset, England, the son of Muriel (née Cross), an acrobat, and Reginald Francis Cleese, who worked in insurance sales. His family's surname was previously "Cheese", but his father changed his surname to "Cleese" in 1915, upon joining the army.

Cleese was educated at St Peter's Preparatory School, Weston-super-Mare where he was a star pupil, receiving a prize for English and doing well at sports including cricket and boxing. At 13 he received an exhibition to Clifton College, an English public school in Bristol, he was a tall child and was well over 6ft when he arrived there.

After leaving school he went back to his prep school to teach science before taking up a place he had won at Downing College, Cambridge where he read Law and joined the Cambridge Footlights Revue. It was there that he met his future writing partner Graham Chapman. Cleese wrote extra material for the 1961 Footlights Revue I Thought I Saw It Move, and was Registrar for the Footlights Club during 1962, as well as being one of the cast members for the 1962 Footlights Revue Double Take! He graduated from Cambridge in 1963 with a 2:1 Degree.

Cleese had started his acting career as part of the Cambridge Footlights revue cast of 1963 and later on went to the US to perform on and off-Broadway. While working there, he not only met future Python member Terry Gilliam, but also American actress Connie Booth, whom he married on February 20, 1968.

Cleese was one of the script writers, as well as being a member of the cast for the 1963 Footlights Revue A Clump of Plinths, which was so successful during the Edinburgh Fringe Festival that its name was changed to Cambridge Circus, was taken to West End in London, and then on a tour of New Zealand and Broadway, with the cast also appearing in some of the revue sketches on The Ed Sullivan Show in September 1964.

As Cleese's comic reputation grew, he was soon offered a position as a writer with BBC Radio, where he worked on several programmes, most notably as a sketch writer for The Dick Emery Show. The success of the Footlights Revue led to the recording of a short series of half-hour radio programmes, called I'm Sorry, I'll Read That Again, which was so popular that the BBC commissioned a regular series with the same title.

After his return to England, Cleese started performing as a cast member of the highly successful BBC Radio show I'm Sorry, I'll Read That Again, which ran from 1965 to 1974. In many episodes, he is credited as "John Otto Cleese".

In 1965, Cleese and Chapman began writing on The Frost Report. The writing staff chosen for The Frost Report consisted of a number of writers and performers who would go on to make names for themselves in comedy. They included future Goodies Bill Oddie and Tim Brooke-Taylor, and also Frank Muir, Barry Cryer, Marty Feldman, Ronnie Barker, Ronnie Corbett, Dick Vosburgh and future Python members Eric Idle, Terry Jones and Michael Palin. It was while working on The Frost Report, in fact, that the future Pythons developed the writing styles that would make their collaboration significant.

Cleese and Chapman's sketches often involved authority figures, some of which were performed by Cleese, while Jones and Palin were both infatuated with filmed scenes that open with idyllic countryside panoramas. Idle was one of those charged with writing David Frost's monologue. It was during this period that Cleese met and befriended influential British comedian Peter Cook.

Such was the popularity of the series that in 1966 Cleese and Chapman were invited to work as writers and performers with Brooke-Taylor and Feldman on At Last the 1948 Show, during which time the Four Yorkshiremen sketch was written by all four writers/performers (the Four Yorkshiremen sketch is now better known as a Monty Python sketch). John Cleese and Graham Chapman also wrote episodes of Doctor in the House.

These series were successful and, in 1969, Cleese and Chapman were offered their very own series. However, due to Chapman's alcoholism, Cleese found himself bearing an increasing workload in the partnership and was therefore unenthusiastic about doing a series with just the two of them. He had found working with Palin on The Frost Report an enjoyable experience, and invited him to join the series.

Palin had previously been working on Do Not Adjust Your Set, with Idle and Jones, and Terry Gilliam doing animations. The four of them had, on the back of the success of Do Not Adjust Your Set, been offered a series for ITV, which they were waiting to begin when Cleese's offer arrived. Palin agreed to work with Cleese and Chapman in the meantime, bringing with him Gilliam, Jones and Idle.

Monty Python's Flying Circus ran for four series from October 1969 to December 1974 on BBC Television. Cleese's two primary characterizations were as a sophisticate and a stressed-out loony. He portrayed the former as a series of announcers, TV show hosts, government officials (qv. "The Ministry of Silly Walks"), et al. The latter is perhaps best represented in the "Cheese Shop", and by Cleese's Mr Praline character, the man with a dead Norwegian Blue parrot and a menagerie of other animals all named "Eric".

He was also known for his working-class "Sergeant Major" character, who worked as a Police Sergeant, Roman Centurion, etc. he is also seen as the opening announcer, with the now famous line: "And now for something completely different".