After a brief career as an actor, he became a novelist in his early twenties with the publication of Monday Morning (1925), written when he was nineteen. Craven House (1926) and Twopence Coloured (1928) followed, but his first real success was the play Rope (1929, known as Rope's End in America).
The Midnight Bell (1929) is based upon Hamilton's falling in love with a prostitute, and was later published along with The Siege of Pleasure (1932) and The Plains of Cement (1934) as the semi-autobiographical trilogy 20,000 Streets Under the Sky (1935).
Hamilton disliked many aspects of modern life. He was disfigured badly when he was run over by a car in the late 1920s: the end of his novel Mr Stimpson and Mr Gorse (1953), with its vision of England smothered in metal beetles, reflects his loathing of the motor car. However, despite some distaste for the culture in which he operated, he was a popular contributor to it. His two most successful plays, Rope and Gas Light (1938, known as Angel Street in America), made Hamilton wealthy and were also successful as films: the British-made Gaslight (1940) and the 1944 American remake, and Alfred Hitchcock's Rope (1948).
Hangover Square (1941) is often judged his most accomplished work and still sells well in paperback, and is regarded by contemporary authors such as Iain Sinclair and Peter Ackroyd as an important part of the tradition of London novels. Set in Earls Court where Hamilton himself lived, it deals with both alcohol-drinking practices of the time and the underlying political context, such as the rise of fascism and responses to it. Hamilton became an avowed Marxist, though not a publicly declared member of the Communist Party of Great Britain. During the 1930s, like many other authors, Hamilton grew increasingly angry with capitalism and, again like others, felt that the violence and fascism of Europe during the period indicated that capitalism was reaching its end: this encouraged his Marxism and his novel Impromptu in Moribundia (1939) was a satirical attack of capitalist culture.
During his later life, Hamilton developed in his writing a misanthropic authorial voice which became more disillusioned, cynical and bleak as time passed. The Slaves of Solitude (1947), was his only work to deal directly with the Second World War, and he preferred to look back to the pre-war years. His Gorse Trilogy - three novels about a devious sexual predator and conman - are not generally well thought of critically, although Graham Greene said that the first was 'the best book written about Brighton' and the second (Mr. Stimpson and Mr. Gorse) is regarded increasingly as a comic masterpiece. The hostility and negativity of the novels is also attributed to Hamilton's disenchantment with the utopianism of Marxism and depression. The trilogy is comprised of The West Pier (1952), Mr. Stimpson and Mr. Gorse (1953), dramatized as The Charmer in 1987, and in 1955 Hamilton's last work published, Unknown Assailant, which is short and was partly dictated as Hamilton was drunk. The Gorse Trilogy was first published in a single volume during 1992.
Hamilton had begun to consume alcohol excessively while still a relatively young man. After a declining career and melancholia, he died in 1962 of cirrhosis of the liver and kidney failure, in Sheringham, Norfolk. He was married twice, firstly to Lois Marie Martin in 1930, and a year after divorcing Lois, to Lady Ursula Chetwynd-Talbot in 1954.