Lewis was reputedly born on a yacht off the Canadian province of Nova Scotia. His mother was British, his father American. He was educated in England, first at Rugby School, then at the Slade School of Art in London, before spending most of the 1900s travelling around Europe and studying art in Paris.

Mainly resident in England from 1908, Lewis published his first work (accounts of his travels in Brittany) in Ford Madox Ford's The English Review in 1909. He was an unlikely founder-member of the Camden Town Group in 1911. In 1912 he exhibited his cubo-futurist illustrations to Timon of Athens (later issued as a portfolio, the proposed edition of Shakespeare's play never materialising) and three major oil-paintings at the Second Post-Impressionist exhibition. This brought him into close contact with the Bloomsbury Group, particularly Roger Fry and Clive Bell, with whom he soon fell out. It was in the years 1913-15 that he found the painting style for which he is best known today, a style which his friend Ezra Pound dubbed Vorticism. Lewis found the strong structure of Cubist painting appealing, but said it did not seem "alive" compared to Futurist art, which, conversely, lacked structure. Vorticism combined these two movements in a strikingly dramatic critique of modernity. In his early works, particularly versions of village life in Brittany showing dancers (ca. 1910-12), Lewis may have been influenced by the process philosophy of Henri Bergson, whose lectures he attended in Paris. Though he was later savagely critical of Bergson, he admitted in a letter to Theodore Weiss (19 April 1949) that he 'began by embracing his evolutionary system'. After a brief tenure at the Omega Workshops, Lewis had a disagreement with the founder Roger Fry and left with several Omega artists to start a competing workshop called The Rebel Art Centre.

After the Vorticists' only exhibition in 1915, the movement broke up, largely as a result of World War I. Lewis was posted to the western front, and served as a second lieutenant in the Royal Artillery. After the Battle of Ypres in 1917, he was appointed as an Official War Artist for both the Canadian and British governments, beginning work in December 1917. For the Canadians he painted A Canadian Gun-Pit (1918, National Gallery of Canada, Ottawa) from sketches made on Vimy Ridge. For the British he painted one of his best known works, A Battery Shelled (1919, Imperial War Museum), drawing on his own experience in charge of a six-inch howitzer at Passchendaele. Lewis exhibited his war drawings and some other paintings of the war in an exhibition, 'Guns', in 1918. His first novel Tarr was also published in book-form in 1918, having been serialised in The Egoist during 1916-17. It is widely regarded as one of the key modernist texts. Lewis later documented his experiences and opinions of this period of his life in the autobiographical Blasting and Bombardiering (1937), which also covered his post-war activities.

After the war, Lewis resumed his career as a painter, with a major exhibition, Tyros and Portraits at the Leicester Galleries in 1921. 'Tyros' were satirical caricatural figures intended by Lewis to comment on the culture of the 'new epoch' that succeeded the First World War. A Reading of Ovid and Mr Wyndham Lewis as a Tyro are the only surviving oil paintings from this series. As part of the same project, Lewis also launched his second magazine, The Tyro, of which there were only two issues. The second (1922) contained an important statement of Lewis's visual aesthetic: 'An Essay on the Objective of Plastic Art in our Time'. It was during the early 20s that he perfected his incisive draughtsmanship. But by the late 1920s, he was not painting so much, instead concentrating on writing. He launched yet another magazine, The Enemy (three issues, 1927-29), largely written by himself and declaring its belligerent critical stance in its title. His major theoretical and cultural statement from this period is The Art of Being Ruled (1926). Time and Western Man (1927) is a cultural and philosophical discussion that includes a penetrating critique of James Joyce which is still read. Philosophically, Lewis attacked the "time philosophy" of Bergson, Samuel Alexander, Alfred North Whitehead and others.

In The Apes of God (1930) he wrote a biting satirical attack on the London literary scene, including a long chapter caricaturing the Sitwell family, which did not help his position in the literary world. His book Hitler (1931), which defended Hitler as a harmless vegetarian whose peaceful programme was threatened by communist street violence, confirmed his unpopularity among liberals and anti-fascists, especially after Hitler came to power in 1933. He later wrote The Hitler Cult (1939), a book which firmly revoked his earlier willingness to entertain Hitler, but the damage was done, and Lewis was to remain an isolated figure. In the 1930s Auden called him "that lonely old volcano of the Right."

Lewis's novels are known among some critics for their satirical and hostile portrayals of Jews, homosexuals, lesbians and other minorities. Since the publication of Anthony Julius's T. S. Eliot, Anti-Semitism, and Literary Form (1995, revised 2003), where Lewis's anti-semitism is described as 'essentially trivial', this view is no longer taken seriously. The 1918 novel Tarr was revised and republished in 1928 with a new Jewish character given a key role in causing conflict among the other European protagonists, but it would be an overstatement to describe this as 'anti-semitism'. The Apes of God (1930) contains numerous Jewish figures, including the modernist author and editor Jamesjulius Ratner, a portrait which blends anti-semitic stereotype with historical literary figures (John Rodker and James Joyce). These Jewish figures all gleefully assist the decline of the weak English liberals who inhabit Bloomsbury.

During the years 1934-37 he wrote The Revenge for Love (1937) set in the period leading up to the Spanish Civil War, regarded by many as his best novel. Yet this novel too hinges on an anti-semitic plot, with Jewish art-forgers destroying the values of Western art while Jewish gun-runners foment civil war.

An interesting book of critical essays belongs to this period: Men without Art (1934). It includes one of the first commentaries on Faulkner, and a famous essay on Hemingway.

Despite being better known for his writing than his painting in his later years, paintings from the 1930s and 1940s constitute some of his best-known work. They are mainly portraits, and include pictures of Edith Sitwell (1923-36), T. S. Eliot (1938 and again in 1949) and Ezra Pound (1939). The Surrender of Barcelona (1936-37) makes a significant statement about the Spanish Civil War.

Lewis spent World War II in the United States and Canada. Artistically the period is mainly important for the series of watercolour fantasies around the theme of creation that he produced in Toronto in 1941-2. He returned to England in 1945. By 1951, he was completely blind. In 1950 he published the autobiographical Rude Assignment, and in 1952 a book of essays on writers such as Orwell, Sartre and Malraux, entitled The Writer and the Absolute. This was followed by the semi-autobiograpical novel Self Condemned (1954), a major late statement. He died in 1957. Always interested in Roman Catholicism, he nevertheless never converted. In recent years there has been a renewal of critical and biographical interest in Lewis and his work, and he is now regarded as a major British artist and writer of the twentieth century.