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Humphrys was born in Splott, a poor working class district of central Cardiff, son of Winifred Mary (Matthews), a hairdresser, and Edward George Humphrys, a self employed French polisher. He was one of five children. His parents encouraged him to do his homework and he passed the eleven plus exam. He became a pupil at Cardiff High School (then a grammar school), but he did not fit in to the middle class environment there. He was an average pupil and left school at the age of 15 years to become a teenage reporter on the Penarth Times. He later joined the Western Mail.

Humphrys joined TWW, a commercial television channel based in Wales. He joined the BBC in 1966 as the district reporter for Liverpool and the Northwest, where he reported the dock strikes of that time, sometimes for the national news. He then worked as a foreign correspondent initially having to go abroad and leave his family for six to nine month periods, at a time when his children were still young and growing up. Later he took his family with him to the United States and South Africa where he was sent to start news bureaux. He reported the resignation of Richard Nixon in 1974 on television by satellite from the United States, the execution of Gary Gilmore in 1977, and later, when based in South Africa, he covered the transformation of Rhodesia into Zimbabwe.

Humphrys became disillusioned with living in hotels and life on-the-road as a foreign correspondent, and so he returned to London in 1980 to take up the post of BBC Diplomatic Correspondent. In 1981 he became the main presenter of the BBC's flagship Nine O'Clock News. This appointment marked a change in the BBC's approach to news broadcasting. With the appointment of Humphrys and John Simpson, the presenters of the news became part of the process of preparing the broadcast, rather than just reading a prepared script as with previous presenters. The work involved going to many meetings, working late and reading from an autocue, so in 1986 he immediately accepted a job on Today when he was unexpectedly offered it at one day at about midnight by telephone. The job had become available because John Timpson was going to retire at the end of 1986. He started presenting Today in January 1987 joining Brian Redhead. He still made occasional appearances fronting BBC TV news bulletins in the 1990s. During the 1991 Gulf War he was a volunteer presenter on the BBC Radio 4 News FM service. From 1993 he presented the weekly On The Record political TV show until its demise in 2002.

He made the headlines on 28 August 2004 for giving the yearly MacTaggart lecture in which he made scathing criticism of the 'dumbing down' of British television. He criticised reality shows such as Big Brother, as well as the increasing violence in British soap operas. He made these criticisms after five years of being without a television set, and in the context of re-acquainting himself with the medium after the prolonged gap. Ironically, Humphrys is also the presenter of the revived version of Mastermind, which has also been accused of 'dumbing down'. After his criticism of reality television, Humphrys appeared the following year in Art School, a show which followed a celebrity reality format.

Humphrys attracted further controversy in September 2005 when he allegedly branded all politicians as liars and made comments about Tony Blair, Gordon Brown, and John Prescott in an after-dinner speech which was subsequently leaked to The Times by Tim Allan, a former aide to the Prime Minister. On 6 September 2005, Humphrys was censured by the Corporation for his use of "inappropriate and misguided" language.

Humphrys has also presented Panorama. He has won many industry awards, including being named Journalist of the Year in February 2000 at an awards ceremony organised by The House Magazine and Channel 4; the Gold Sony Radio Award in 2003; and a silver platter for Crystal Clear Broadcasting from the Plain English Campaign.

John Humphrys has written several books, including Lost for Words, in which he criticizes what he sees as the widespread misuse of the English language, plus 'Devil's Advocate', 'Beyond Words', 'The Great Food Gamble' and 'In God We Doubt: Confessions Of A Failed Atheist'.

Humphrys is an agnostic, but has a curiosity to test his agnosticism and challenge established religions to see if they can restore his childhood belief in God. In 2006, he presented a BBC Radio 4 programme, titled "Humphrys in Search of God" where he spoke to leading British authorities on Christianity, Judaism and Islam to try and restore his faith.

Despite his reputation, Humphrys is prepared to send himself up: for example, when he appeared on the light entertainment programme Top Gear driving a Peel P50 around BBC White City.

On 12 November 2009 he became the only person to replace David Dimbleby as the host of Question Time when Dimbleby was recovering from a minor farming injury.

Criticism

Humphrys has occasionally been criticised for his forthright interviewing style: for example, in March 1995 after being interviewed on Today the former Conservative Cabinet Minister, Jonathan Aitken, accused him of "poisoning the well of democratic debate", although Aitken was not supported by his fellow Cabinet Ministers, Kenneth Clarke and Douglas Hurd when they were interviewed by Humphrys on the Today programme, on the following Monday.

Humphrys has been criticised for receiving shares in the poll organisation YouGov for which he wrote a column. Humphrys denied that there was a conflict of interest between his role as newscaster and that of shareholder of a company, the reports of which are often cited in the news on the BBC.

On Friday 9 May 2008 Humphrys interviewed Richard Dawkins regarding a recent speech by Cormac Murphy O'Connor. Dawkins alleged that Humphrys had a "double standard" of not requiring evidence of a clergyman, despite his reputation for demanding evidence of politicians. Dawkins asked Humphrys to explain why. Humphrys, arguing that the difference was that such evidence cannot be asked of a man of faith, felt that the interview was being made "about him" by Dawkins's question.

Humphrys married Edna Wilding (born August 1942) in 1964 and they soon had two children, a son and daughter, Christopher and Catherine. This marriage broke down in the late 1980s. Wilding died of cancer in September 1997 in Glamorgan, South Wales; Humphrys described her last days in a hospice in his book Devil's Advocate. Christopher is now a professional cellist.

On 2 June 2000, when he was 56 years of age, Humphrys and his second wife, Valerie Sanderson, had a son, Owen James. Sanderson was a newsreader with Spotlight then BBC News 24 and is now a radio producer. Humphrys had a reverse vasectomy. He referred to these facts on 31 October 2006 on BBC Radio 4 in the programme Humphrys in Search of God. He is now in a relationship with the Observer journalist Catherine Bennett.

In 2005 he founded the Kitchen Table Charities Trust, a charity that funds projects to help some of the poorest people on the planet.

Humphrys was a guest on the BBC Radio 4 show Desert Island Discs on 6 January 2008. His favourite record of the eight he selected for the show was Elgar’s Cello Concerto; he chose the biggest poetry anthology possible as his book and a cello as a luxury on the desert island.

Humphrys' brother, Bob Humphrys, was a sports television presenter on BBC Wales Today. He died of lung cancer in Cardiff on 19 August 2008, aged 56.