The son of a French father and an English mother, Barbusse was born in Asnières-sur-Seine, France in 1873. Although he grew up in a small town, he left for Paris in 1889 at age 16. In 1914, at the age of 41, he enlisted in the French Army and served against Germany in World War I. Invalided out of the army three times, Barbusse would serve in the war for 17 months, until the end of 1915, when he was permanently moved into a clerical position due to pulmonary damage, exhaustion, and dysentery.

Barbusse first came to fame with the publication of his novel Le Feu (translated as Under Fire) in 1916, which was based on his experiences during World War I. By this time, Barbusse had become a pacifist, and his writing demonstrated his growing hatred of militarism. Le Feu drew criticism at the time for its harsh naturalism, but won the Prix Goncourt.

In January, 1918 he left France and moved to the city of Moscow, Russia where he married a Russian woman and joined the Bolshevik Party. The novel Clarté is about an office worker who, while serving in the army, begins to realize that the imperialist war is a crime.

The Russian Revolution had significant influence on the life and work of Barbusse. He joined the French Communist Party in 1923 and later traveled back to the Soviet Union. His later works, Manifeste aux Intellectuels (Elevations) (1930) and others show a more revolutionary standpoint. Of these, the 1921 Le Couteau entre les dents (The Knife Between My Teeth) marks Barbusse's siding with Bolshevism and the October Revolution. Barbusse characterized the birth of Soviet Russia as "the greatest and most beautiful phenomenon in world history." The book "Light from the Abyss" (1919) and the collection of articles "Words of a Fighting Man" (1920) contain calls for the overthrow of capitalism. In 1925, Barbusse published "Chains", showing history as the unbroken chain of suffering of people and their struggle for freedom and justice. In the publicistic book "The Butchers" he exposes the White Terror in the Balkan countries.

In 1927 Barbusse was a participant in the Congress of Friends of the Soviet Union in Moscow. He led the World Congress Against Imperialist War (Amsterdam, 1932) and headed the World Committee Against War and Fascism, founded in 1933. He took part in the work of the International Youth Congress (Paris, 1933) and the International Congress of Writers in Defense of Culture. In the 1920s and 1930s, he also edited the periodicals Monde and Progrès Civique, which published some of the first writings of George Orwell.

In 1934 Barbusse sent Egon Kisch to Australia to represent the International Movement Against War and Fascism as part of his work for the Comintern. The resulting unsuccessful exclusion of Egon Kisch from Australia by the Conservative Australian Government succeeded in energising Communism in Australia and resulted in Kisch staying longer than Barbusse had intended.

An associate of Romain Rolland and editor of Clarté, he attempted to define a proletarian literature, akin to Proletkult and Socialist realism. Barbusse was the author of a 1936 biography of Joseph Stalin, titled Staline: Un monde nouveau vu à travers un homme (Stalin. A New World Seen Through the Man). Barbusse subsequently led a violent press campaign against his former friend Panait Istrati - a Romanian writer who had expressed criticism of the Soviet state. Barbusse in turn was harshly criticized for his admiration of Stalin and his propagandistic activities on behalf of Soviet Russia by his former comrade Victor Serge, who noted that Barbusse had dedicated a book to Leon Trotsky before Stalin had definitively won the power struggle against Trotsky, only to denounce Trotsky as a traitor after the latter's fall from power. Serge called Barbusse a hypocrite who was determined to be on the winning side.

Barbusse was an Esperantist, and was honorary president of the first congress of the Sennacieca Asocio Tutmonda. In 1921, he wrote an article for Esperanto journal, Esperantista Laboristo. ("Esperantist worker")

While writing a second biography of Stalin in Moscow, Barbusse fell ill with pneumonia, and died on August 30, 1935 He is buried in Le Père Lachaise Cemetery, Paris. His grave has been vandalized in recent years, with many people mistaking his tombstone for Oscar Wilde's.

In the foreword to I saw it Happen, a 1942 collection of eye-witness accounts of the war, Lewis Gannet wrote: "(...) We shall be hearing and reading of this war for decades to come. No one of us can yet guess who will be its Tolstoy, its Barbusses, its Remarques and its Hemingways".

The parc Henri Barbusse was the site of the Château d'Issy.