Karl Pilkington grew up in Sale, Greater Manchester, and spent much of his childhood in Porthmadog, Wales, due to his father's work. He was also educated in Manchester. Ricky Gervais and Stephen Merchant contacted Pilkington's school after a conversation during their XFM show and discovered that he attained only one GCSE for History, for which he achieved an "E" grade. Pilkington was surprised and upset at this as he recalled sitting through several other GCSE exams; however a failure to register for them was offered as an explanation by Gervais and Merchant for his lack of other grades.

In December 2005, Pilkington stood in for two BBC 6 Music shows for Nemone, and co-presented the shows with Russell Brand. They proved so popular that by the following April, Brand was working as a permanent DJ at BBC 6 Music, which was the forerunner to his Radio 2 show.

Pilkington has homes in Hampstead, London and Deal, Kent.

He is a supporter of Manchester United.

On 24 April 2006, The New York Times ran an article about Ricky Gervais and the podcast which described Pilkington's behaviour as a well-executed "deadpan comedian" routine which "crosses Ali G and Steven Wright".

Merchant and Gervais themselves have repeatedly denied claims that Pilkington's comic persona is their creation. In an on-air response to similar claims made by Chris Campling during a broadcast on Xfm, Merchant stated that he would be "ashamed" if the radio show were scripted, adding that "If we had created Karl, I would not have squandered a character that good on this poxy radio station". Gervais concurred, pointing out as a comparison that writing a single series worth of half-hour episodes of shows such as The Office and Extras took the two up to a year.

As a result of the success of The Ricky Gervais Show podcasts in particular, Pilkington has become a cult celebrity. Pilkington has often been mentioned in interviews given by Gervais, and he is often on the receiving end of Gervais' practical jokes. When asked who was the funniest person he knew, Gervais said that Karl Pilkington was "the funniest man alive in Britain today." In addition, Pilkington appears in a twenty-minute interview on Gervais' live stand-up comedy DVD, Politics. The DVD of Gervais' film The Invention of Lying contains a short film called "Meet Karl Pilkington", entirely devoted to documenting Pilkington's humiliating non-speaking role in the DVD extra caveman feature "The Dawn of Lying". He was also invited to be an extra on the final episode of Gervais' and Merchant's Extras.

Pilkington further spread his celebrity after uttering the phrase "I could eat a knob at night" on the podcast The Ricky Gervais Show. The phrase came up during a conversation about how contestants on I'm a Celebrity, Get Me Out of Here! had to eat a kangaroo's penis. Gervais and Merchant latched onto Pilkington's words and encouraged his listeners to sample that sound bite and mix it into dance songs that could be played in night clubs. The phrase "I could eat a knob at night" has since spawned dance music remixes, T-shirts and other merchandise. Reuters, commenting on this issue, described Pilkington as a "phenomenon" who had made "Internet history".

Pilkington has also worked independently of Gervais and Merchant on a number of projects. He appeared as a guest on the Nation 277 series Flipside TV; he has featured several times as a guest on BBC series The Culture Show; he has appeared in several short films as part of the Channel 4 initiative "3 Minute Wonders"; and Channel 4's "Karl Pilkington - Satisfied Fool" was broadcast 22 October 2007. In "Satisfied Fool" he took part in a MENSA IQ test: just before the end credits his IQ was revealed to be 83. Pilkington has also performed voice-over work for such clients as Vodafone, HMV, Sony PSP, W H Smith, Polycell, Wickes and Unilever.

In September 2010 Karl Pilkington featured in a television series produced by Ricky Gervais and Stephen Merchant called An Idiot Abroad on Sky1. The series documented a global adventure by Karl instigated by Gervais and Merchant in order to take Pilkington ‘out of his comfort zone’.The series consists of 8, one hour-long, episodes tracking Karl as he negotiates the ‘Wonders of the World’ in an attempt to broaden his horizons. The series is accompanied by a book published by Canongate and co-written by Gervais and Stephen Merchant.

Pilkington has written a number of semi-factual and fictitious books upon quitting from his job as producer at XFM.

• The World of Karl Pilkington (2006)
• Happyslapped by a Jellyfish (2007)
• What I've Learnt So Far (2008)
• The Travel Diaries of Karl Pilkington (2010)