Sillitoe left school at the age of 14, having failed at the entrance examination to grammar school. He worked at the Raleigh factory for the next four years, spending his free time reading prodigiously and being a "serial lover of local girls". He then joined the Air Training Corps in 1942 then the Royal Air Force, albeit too late to serve in the Second World War. He served as a wireless operator in Malaya during the Emergency. After returning to Britain, he was planning to enlist in the Royal Canadian Air Force, but was discovered to have tuberculosis and spent 16 months in an RAF hospital.

Pensioned off at the age of 21 on 45 shillings (£2.25) a week, he lived in France and Spain for seven years in an attempt to recover. In 1955, while living in Mallorca with the American poet Ruth Fainlight, whom he married in 1959, and in contact with the poet Robert Graves, Sillitoe started work on Saturday Night and Sunday Morning, which was published in 1958. Influenced in part by the stripped-down prose of Ernest Hemingway, the book conveys the attitudes and situation of a young factory worker faced with the inevitable end of his youthful philandering. As with John Osborne's Look Back in Anger and John Braine's Room at the Top, the novel's real subject was the disillusionment of post-war Britain and the lack of opportunities for the working class. It was adapted as a film by Karel Reisz in 1960, with Albert Finney as Arthur Seaton; the screenplay was written by Sillitoe.

Sillitoe's story The Loneliness of the Long Distance Runner, which concerns the rebellion of a borstal boy with a talent for running, won the Hawthornden Prize in 1959. It was also adapted into a film, in 1962, directed by Tony Richardson and starring Tom Courtenay. Sillitoe wrote the screenplay.

In the 1960s Sillitoe was celebrated in the Soviet Union as a spokesman for the "oppressed worker" in the West. Invited to tour the country, he visited several times in the 1960s and in 1968 he was asked to address the Congress of Soviet Writers' Unions, where he denounced Soviet human rights abuses, many of which he himself had witnessed.

In 1990 Sillitoe was awarded an honorary degree from Nottingham Trent University. The city's older Russell Group university, the University of Nottingham, also awarded him an honorary D.Litt in 1994. In 2006 his best-known play was staged at the university's Lakeside Arts theatre in an in-house production.

Sillitoe wrote many novels and several volumes of poems. His autobiography, Life Without Armour, which was critically acclaimed on publication in 1995, offers a view of his squalid childhood. In an interview Sillitoe claimed, "A Writer, if he manages to earn a living at what he's doing, even if it's a very poor living, acquires some of the attributes of the old-fashioned gentleman (if I can be so silly)."

Sillitoe was elected a Fellow of the Royal Society of Literature in 1997.

Gadfly in Russia, an account of his travels in Russia spanning 40 years, was published in 2007. In 2008 London Books republished A Start in Life in its London Classics series and to mark the author's 80th birthday. Sillitoe appeared on Desert Island Discs on BBC Radio 4 on 25 January 2009.

Sillitoe died of cancer on 25 April 2010 at Charing Cross Hospital in London. He was 82. He is buried in Highgate Cemetery.