Denis Charles Pratt was born in Sutton, South London, on Christmas Day 1908, the fourth child of solicitor Spencer Charles Pratt (1871–1931) and former governess Frances Marion Pratt (née Phillips; 1873–1960). His elder siblings were Katherine (1901–1976), Gerald (1902–1983) and Lewis (1907–1968). He changed his name to Quentin Crisp in his twenties after leaving home and cultivating his effeminate appearance to a standard that both shocked contemporary Londoners and provoked homophobic attacks.

By his own account Crisp was effeminate in behaviour from an early age and found himself the object of teasing at Kingswood House School in Epsom, from which he won a scholarship to Denstone College, Uttoxeter, in 1922. After leaving school in 1926 Crisp studied journalism at King's College London but failed to graduate in 1928 going on to take art classes at the Regent Street Polytechnic.

Crisp left home to move to the centre of London at the end of 1930 and after dwelling in a succession of flats found a bed-sitting room in Denbigh Street, Pimlico, where he "held court with London's brightest and roughest characters." His outlandish appearance – he wore bright make-up, dyed his long hair crimson, painted his fingernails and wore sandals to display his painted toe-nails – brought admiration and curiosity from some quarters, but generally attracted hostility and violence from strangers passing him in the streets.

In 1940 he moved into a first-floor flat at 129 Beaufort Street, Chelsea, a bed-sitting room that he occupied until he emigrated to the United States in 1981. In the intervening years he never attempted any housework, writing famously in his memoir The Naked Civil Servant: "After the first four years the dirt doesn't get any worse."

Crisp attempted to join the British army at the outbreak of the Second World War, but was rejected and declared exempt by the medical board on the grounds that he was "suffering from sexual perversion". He remained in London during the 1941 Blitz, stocked up on cosmetics, purchased five pounds of henna and paraded through the black-out, picking up G.I.s, whose kindness and open-mindedness inspired his love of all things American.

Crisp left his job as an engineer's tracer in 1942 to become a model in life classes in London and the Home Counties. He continued posing for artists for the next 30 years.

Crisp had published three short books by the time he came to write The Naked Civil Servant at the urging of his agent, Donald Carroll. Crisp wanted to call it I Reign in Hell, a reference to Paradise Lost ("Better to reign in Hell, than serve in Heaven"), but Carroll insisted on The Naked Civil Servant, an insistence that later gave him pause when he offered the manuscript to Tom Maschler of Jonathan Cape on the same day that Desmond Morris delivered The Naked Ape. The book was published in 1968 to generally good reviews. Subsequently Crisp was approached by the documentary-maker Denis Mitchell to be the subject of a short film in which he was expected to talk about his life, voice his opinions and sit around in his flat filing his nails.

When his autobiography was reprinted in 1975 after the success of the television version of The Naked Civil Servant, Gay News commented that the book should have been published posthumously (Crisp commented that this was their polite way of telling him to drop dead). Gay rights campaigner Peter Tatchell said he had met Crisp in 1974 and alleged that he was not sympathetic to the Gay Liberation movement of the time. Tatchell said Crisp asked him: "What do you want liberation from? What is there to be proud of? I don't believe in rights for homosexuals."

Crisp also acted on television and in films. He made his debut as a film actor in the Royal College of Art's low-budget production of Hamlet (1976). Crisp played Polonius in the 65-minute adaptation of Shakespeare's play, supported by Helen Mirren, who doubled as Ophelia and Gertrude. He appeared in the 1985 film The Bride, which brought him into contact with Sting, who played the lead role of Baron Frankenstein. He appeared on the television show The Equalizer in the 1987 episode "First Light" and as the narrator of Director Richard Kwietniowski's short film Ballad of Reading Gaol (1988), based on the poem by Oscar Wilde. Four years later he was cast in a lead role, and got top billing, in the low-budget independent film Topsy and Bunker: The Cat Killers, playing the door-man of a flea-bag hotel in a run-down neighbourhood quite like the one he dwelled in. According to Director Thomas Massengale, Crisp was a delight to work with.

By now Crisp was a theatre-filling raconteur. His one-man show sold out the Duke of York's Theatre in London in 1978. Crisp then took the show to New York. His first stay in the Hotel Chelsea coincided with a fire, a robbery, and the death of Nancy Spungen. Crisp decided to move to New York permanently and set about making arrangements. In 1981, he arrived with few possessions and found a small apartment on East 3rd Street in Manhattan's East Village.

Sting dedicated his song "Englishman in New York" (1987) to Crisp. He had remarked jokingly "that he looked forward to receiving his naturalisation papers so that he could commit a crime and not be deported." In late 1986 Sting visited Crisp in his apartment and was told over dinner – and the next three days – what life had been like for a homosexual man in the largely homophobic Great Britain of the 1920s to the 1960s. Sting was both shocked and fascinated and decided to write the song. It includes the lines:

Crisp remained fiercely independent and unpredictable into old age. He caused controversy and confusion in the gay community by jokingly calling AIDS "a fad", and homosexuality "a terrible disease". He was continually in demand from journalists requiring a sound-bite and throughout the 1990s his commentary was sought on any number of topics.

In his 1995 autobiography Take It Like a Man, Boy George discusses how he had felt an affinity towards Crisp during his childhood, as they faced similar problems as young homosexual people living in homophobic surroundings.

In 1997 Quentin Crisp was crowned king of the Beaux Arts ball run by the Beaux Arts Society. He presided alongside Queen Audrey Kargere, Prince George Bettinger and Princess Annette Hunt.

In December 1998 he celebrated his ninetieth birthday performing the opening night of his one-man show, An Evening with Quentin Crisp, at The Intar Theatre on Forty-Second Street in New York City (produced by John Glines of The Glines organisation). A humorous pact he had made with Penny Arcade to live to be a century old, with a decade off for good behaviour, proved prophetic.

Crisp was the subject of a play Resident Alien by Tim Fountain and starring his friend Bette Bourne in 1999. The play opened at the Bush Theatre in London and transferred to New York Theatre Workshop in 2001 where it won two Obies (for performance and design). It went on to win a Herald Angel (Best actor) at the Edinburgh Festival in 2002. Subsequent productions have been seen across the US and Australia. A film of the same name was released by Greycat Films in 1990.

Also in 2009, Crisp's great-nephew, academic and film-maker Adrian Goycoolea, premiered a short documentary, Uncle Denis?, at the 23rd London Lesbian & Gay Film Festival. The film uses interviews with family and previously unseen home movie footage. In collaboration with Crisperanto curator Philip Ward, Goycoolea also created an installation entitled 'Personal Effects' at the 2010 MIX NYC, New York City, which recreated Crisp's New York apartment using his personal effects and included home video footage.

In 2013, with curator Phillip Ward of Crisperanto: The Quentin Crisp Archives, the Museum of Arts and Design, in Manhattan, staged a three-month retrospective on Quentin Crisp entitled Ladies and Gentlemen, Mr. Quentin Crisp. The retrospective consisted of free screenings of interviews, one man shows, documentaries and other recorded media.

In the 2016 Ghostbusters reboot Bill Murray explicitly based the dress style of his character (Martin Heiss) on Quentin Crisp.