Born in Chicago, Illinois, Dos Passos was the illegitimate son of John Randolph Dos Passos (1844 – 1917), a distinguished lawyer of Madeiran Portuguese descent, and Lucy Addison Sprigg Madison of Petersburg, Virginia. The elder Dos Passos was married with a son several years older than John. John's father married his mother after his wife died in 1910, although he refused to acknowledge his second son for another two years, until John was 16. John Randolph Dos Passos was an authority on trusts and a staunch supporter of the powerful industrial conglomerates his son would come to oppose in his fictional works of the 1920s and 30s.

The younger Dos Passos received a first class education, enrolling at The Choate School (now Choate Rosemary Hall) in Wallingford, Connecticut, in 1907 under the name John Roderigo Madison, then traveling with a private tutor on a six month tour of France, England, Italy, Greece, and the Middle East to study the masters of classical art, architecture, and literature.

In 1912 he attended Harvard University. Following his graduation in 1916 he traveled to Spain to study art and architecture. With World War I raging in Europe and America not yet participating, Dos Passos volunteered in July 1917 for the S.S.U. 60 of the Norton - Harjes Ambulance Corps, along with friends E.E. Cummings and Robert Hillyer. He worked as a driver in Paris and in north central Italy.

By the late summer of 1918, he had completed a draft of his first novel. At the same time, he had to report for duty with the U.S. Army Medical Corps at Camp Crane in Pennsylvania. At war's end, he was stationed in Paris, where the U.S. Army Overseas Education Commission allowed him to study anthropology at the Sorbonne. A character in U.S.A. Trilogy goes through virtually the same military career and stays in Paris after the war.

Considered one of the Lost Generation writers, Dos Passos published his first novel in 1920, One Man's Initiation: 1917. It was followed by an antiwar story, Three Soldiers, which brought him considerable recognition. His 1925 novel about life in New York City, titled Manhattan Transfer, was a commercial success and introduced experimental stream - of - consciousness techniques into Dos Passos's method. These ideas also coalesced into the U.S.A. Trilogy, of which the first book appeared in 1930.

At this point a social revolutionary, Dos Passos came to see the United States as two nations, one rich and one poor. He wrote admiringly about the Wobblies, and the perceived injustice in the criminal convictions of Sacco and Vanzetti, and joined with other notable personalities in the United States and Europe in a failed campaign to overturn their death sentences. In 1928, Dos Passos spent several months in Russia studying their socialist system. He was a leading participator in the April 1935 First Americans Writers Congress sponsored by the Communist leaning League of American Writers, but he eventually balked at the idea of the control that Stalin would have on creative writers in the United States.

In the 1930s, he served on The American Committee for the Defense of Leon Trotsky, commonly known as the "Dewey Commission," with other notable figures such as Sidney Hook, Reinhold Niebuhr, Norman Thomas, Edmund Wilson and chairman John Dewey which had been set up following the first of the Moscow "Show Trials" in 1936. The following year, he wrote the screenplay for the film The Devil is a Woman, starring Marlene Dietrich and directed by Josef von Sternberg, adapted from the 1898 novel La Femme et le pantin by Pierre Louÿs.

In 1937, during the Spanish Civil War, he returned to Spain with his friend Ernest Hemingway, but his views on the Communist movement had already begun to change. Dos Passos broke with Hemingway and Herbert Matthews over their cavalier attitude towards the war and their willingness to lend their names to deceptive Stalinist propaganda efforts, including the cover-up of the Soviet responsibility in the murder of José Robles, Dos Passos's friend and translator of his works into Spanish. (In later years, Hemingway would give Dos Passos the derogatory moniker of "the pilot fish" in his memoirs of 1920s Paris, A Moveable Feast.)

Of communism, Dos Passos would later write: "I have come to think, especially since my trip to Spain, that civil liberties must be protected at every stage. In Spain I am sure that the introduction of GPU methods by the Communists did as much harm as their tank men, pilots and experienced military men did good. The trouble with an all powerful secret police in the hands of fanatics, or of anybody, is that once it gets started there's no stopping it until it has corrupted the whole body politic. I am afraid that's what's happening in Russia."

Dos Passos had attended the 1932 Democratic National Convention and subsequently wrote an article for The New Republic in which he harshly criticized the selection of Franklin Delano Roosevelt as the party's nominee. In the mid 1930s he wrote a series of scathing articles about Communist political theory, and created an idealistic Communist in The Big Money who is gradually worn down and destroyed by group think in the party. As a result of socialism gaining popularity in Europe as a response to Fascism, there was a sharp decline in international sales of his books. Between 1942 and 1945, Dos Passos worked as a journalist and war correspondent covering World War II.

In 1947, he was elected to the American Academy of Arts and Letters. Tragedy struck the same year when an automobile accident killed his wife of 18 years, Katharine Smith, and cost him the sight in one eye. The couple had no children. Dos Passos married Elizabeth Hamlyn Holdridge (1909 – 1998) in 1949, by whom he had an only daughter, Lucy Hamlin Dos Passos (b. 1950).

His politics, which had always underpinned his work, moved to the right, and Dos Passos came to have a qualified, and temporary, sympathy for the goals of Joseph McCarthy in the early 1950s. However, his longtime friend, journalist John Chamberlain, believed that "Dos always remained a libertarian." In 1950s, Dos Passos also contributed to publications such as the libertarian journal The Freeman and the conservative magazine, National Review.

In the same decade, he published the influential study, The Head and Heart of Thomas Jefferson (1954), about which fellow ex-radical Max Eastman wrote: "I think John Dos Passos has done a great service to his country and the free world by lending his talents to this task. He has revived the heart and mind of Jefferson, not by psycho - analytical lucubrations or soulful gush, but in the main by telling story after story of those whose lives and thoughts impinged upon his. And Jefferson's mind and heart are so livingly related to our problems today that the result seems hardly to be history."

Recognition for his significant contribution to literature would come thirty years later in Europe when, in 1967, he was invited to Rome, Italy, to accept the prestigious Antonio Feltrinelli Prize for international distinction in literature. Although Dos Passos's partisans have contended that his later work was ignored because of his changing politics, many critics agree that the quality of his novels declined following U.S.A.

In the 1960s, he actively campaigned for presidential candidates Barry Goldwater and Richard M. Nixon, and became associated with the group Young Americans for Freedom. He continued to write until his death in Baltimore, Maryland in 1970. He is interred in Yeocomico Churchyard Cemetery in Cople Parish, Westmoreland County, Virginia, not far from where he had made his home.
Over his long and successful career, Dos Passos wrote forty-two novels, as well as numerous poems, essays, and plays, and created more than four hundred pieces of art.

His major work is the celebrated U.S.A. trilogy, comprising The 42nd Parallel (1930), Nineteen Nineteen or 1919 (1932), and The Big Money (1936). Dos Passos used experimental techniques in these novels, incorporating newspaper clippings, autobiography, biography and fictional realism to paint a vast landscape of American culture during the first decades of the twentieth century. Though each novel stands on its own, the trilogy is designed to be read as a whole. Dos Passos's political and social reflections in the novel are deeply pessimistic about the political and economic direction of the United States, and few of the characters manage to hold onto their ideals through the First World War.

Before becoming a leading novelist of his day, John Dos Passos sketched and painted. During the summer of 1922, he studied at Hamilton Easter Field's art colony in Ogunquit, Maine. Many of his books published during the ensuing ten years used jackets and illustrations that Dos Passos created. Influenced by various movements, he merged elements of Impressionism, Expressionism, and Cubism to create his own unique style. And his work evolved with his first exhibition at New York's National Arts Club in 1922 and the following year at Gertrude Whitney's Studio Club in New York City.

While Dos Passos never gained recognition as a great artist, he continued to paint throughout his lifetime and his body of work was well respected. His art most often reflected his travels in Spain, Mexico, North Africa, plus the streets and cafés of the Montparnasse Quarter of Paris that he had frequented with good friends Fernand Léger, Ernest Hemingway, Blaise Cendrars, and others. Between 1925 and 1927, Dos Passos wrote plays as well as created posters and set designs for the New Playwrights Theatre in New York City. In his later years, his efforts turned to painting scenes around his residences in Maine and Virginia.

In early 2001, an exhibition titled The Art of John Dos Passos opened at the Queens Borough Library in New York City after which it moved to several locations throughout the United States.

Dos Passos's pioneering works of nonlinear fiction were a major influence in the field. In particular Alfred Döblin's Berlin Alexanderplatz and Jean - Paul Sartre's The Roads To Freedom trilogy show the influence of his methods. In an often cited 1936 essay, Sartre referred to Dos Passos as "the greatest writer of our time." Writer Mary McCarthy reported that The 42nd Parallel was among the chief influences on her own work. In the television documentary, The Odyssey of John Dos Passos, Norman Mailer said simply: “Those three volumes of U.S.A. make up the idea of a 'great American novel.'” Perhaps the best known work partaking of the "collage technique" found in U.S.A. is science fiction writer John Brunner's Hugo Award winning 1968 "non-novel" Stand on Zanzibar, in which Brunner makes use of fictitious newspaper clippings, television announcements, and other "samples" taken from the news and entertainment media of the year 2010. Joe Haldeman's novel Mindbridge also uses the collage technique, as does his short story, "To Howard Hughes: A Modest Proposal."

The John Dos Passos Prize is a literary award given annually by the Department of English and Modern Languages at Longwood University. The prize seeks to recognize "American creative writers who have produced a substantial body of significant publication that displays characteristics of John Dos Passos's writing: an intense and original exploration of specifically American themes, an experimental approach to form, and an interest in a wide range of human experiences."