Siqueiros was born the second of three children in Chihuahua, Mexico, in 1896. His father, Cipriano Alfaro, was well-to-do, and was a descendant of Felipe Alfaro of Portugal. His mother, Teresa Siqueiros, came from a Chihuahua family of musicians, actors, and poets. Siqueiros had two siblings: a sister, Luz, three years older, and a brother Chucho, one year younger. David was four years old when his mother died and his father sent the children to live with their paternal grandparents. Siete Filos, David’s grandfather, would have an especially strong role in his upbringing. However, Cipriano, a devout Catholic, disapproved with the way that his parents had been raising the children in the countryside, so in 1907 he brought them back to live with him in Mexico City. There David attended a biblical school. He credits his first rebellious influence to his sister, who had resisted their father’s religious orthodoxy. Around this time, David was also exposed to new political ideas, mainly along the lines of anarcho-syndicalism. One such political theorist was Dr. Atl, who published a manifesto in 1906 calling for Mexican artists to develop a national art and look to ancient indigenous cultures for inspiration. In 1911 when he was only fifteen years old, Siqueiros was involved in a student strike at the Academy of San Carlos of the National Academy of Fine Arts that protested the school's method of teaching and urged the impeachment of the school's director. Their protests eventually led to the establishment of an “open-air academy” in Santa Anita.

At the age of eighteen, Siqueiros and several of his colleagues from the School of Fine Arts, joined Venustiano Carranza’s Constitutional Army fighting the Huerta government. When Huerta fell in 1914, Siqueiros became entrenched in the “post-revolutionary” infighting, as the Constitutional Army had to battle the political factions of Pancho Villa and Emiliano Zapata for control. His military travels around the country exposed him to Mexican culture and the raw everyday struggles of the working and rural poor. After Carranza’s forces had gained control, Siqueiros briefly returned to Mexico City to paint before traveling to Europe in 1919. First in Paris, he absorbed the influence of cubism, intrigued particularly with Paul Cézanne and the use of large blocks of intense color. While there, he also met Diego Rivera, another Mexican painter in “the big three” just on the brink of a legendary career in muralism, and traveled with him throughout Italy to study the great fresco painters of the Renaissance.

Although many have said that Siqueiros' artistic ventures were frequently “interrupted” by his political ones, Siqueiros himself believed the two were intricately intertwined. By 1921, when he wrote his manifesto in Vida Americana, Siqueiros had already been exposed to Marxism and saw the life of the working and rural poor while traveling with the Constitutional Army. In "A New Direction for the New Generation of American Painters and Sculptors," he called for a "spiritual renewal" to simultaneously bring back the virtues of classical painting while infusing this style with "new values" that acknowledge the “modern machine” and the “contemporary aspects of daily life". The manifesto also claimed that a "constructive spirit" is essential to meaningful art, which rises above mere decoration or false, fantastical themes. Through this style, Siqueiros hoped to create a style that would bridge national and universal art. In his work as well as his writing, Siqueiros sought a social realism that at once hailed the proletariat peoples of Mexico and the world while avoiding the clichés of trendy "Primitivism" and "Indianism".

In 1922, Siqueiros returned to Mexico City to work as a muralist for Álvaro Obregón’s revolutionary government. Then Secretary of Public Education José Vasconcelos made a mission of educating the masses through public art and hired scores of artists and writers to build a modern Mexican culture. Siqueiros, Rivera and Jose Orozco worked together under Vasconcelos, who supported the muralist movement by commissioning murals for prominent buildings in Mexico City. Still, the artists working at the Preparatoria realized that many of their early works lacked the "public" nature envisioned in their ideology. In 1923 Siqueiros helped found the Syndicate of Revolutionary Mexican Painters, Sculptors and Engravers, which addressed the problem of widespread public access through its union paper, El Machete. That year the paper published – "for the proletariat of the world" – a manifesto, which Siqueiros helped author, on the necessity of a "collective" art, which would serve as "ideological propaganda" to educate the masses and overcome bourgeois, individualist art.

Soon after, Siqueiros painted his famous mural Burial of a Worker (1923) in the stairwell of the Colegio Chico. The fresco features an indigenous woman mourning over a coffin, decorated with a hammer and sickle. But as the union became ever more critical of the revolutionary government, which had not instituted the promised reforms, its members faced new threats to cut funding for their art and the paper. A feud within the union over whether to cease publishing El Machete or lose financial support for the mural projects left Siqueiros at the forefront, as Rivera left in protest of the decision to uphold politics over artistic opportunity. Despite being let go from his post under the Department of Education in 1925, Siqueiros remained deeply entrenched in labor activities, in the union as well as the Mexican Communist Party, until he was jailed and eventually exiled in the early 1930s.

In the early 1930s, including his time spent in the Mexican Lecumberri Prison, Siqueiros produced a series of politically themed lithographs, many of which were exhibited in the United States. His lithograph Head was shown at the 1930 exhibition “Mexican Artists and Artists of the Mexican School” at The Delphic Studios in New York City. In 1932, he led an exhibition and conference entitled “Rectifications on Mexican Muralism” at the gallery of the Spanish Casino in Taxco, Mexico. Shortly after, he traveled to New York, where he participated in the Weyhe Gallery’s “Mexican Graphic Art” exhibition. With a team of students, he also completed a mural, known sometimes as Tropical America, in 1932 at the Italian Hall at Olvera Street in Los Angeles. Painting fresco on an outside wall – visible to passersby as well as intentional viewers – forced Siqueiros to reconsider his methodology as a muralist. He wanted the image – an image of an Indian peon being crucified by American oppression – to be accessible from multiple angles. Instead of just constructing “an enlarged easel painting,” He realized that the mural “must conform to the normal transit of a spectator.” Eventually, Siqueiros would develop a mural technique that involved tracing figures onto a wall with an electric projector, photographing early wall sketches to improve perspective, and new paints, spray guns, and other tools to accommodate the surface of modern buildings and the outdoor conditions. He was unceremoniously deported from the United States for political activity the same year.

Back to New York in 1936, he was the guest of honor at the “Contemporary Arts” exhibition at the St. Regis gallery. There he also ran a political art workshop in preparation for the 1936 General Strike for Peace and May Day parade. The young Jackson Pollock attended the workshop and helped build floats for the parade. Continuing to produce several works throughout the late 1930s – such as Echo of a Scream (1937) and The Sob (1939), both now at the Museum of Modern Art in New York – Siqueiros also led a number of experimental art workshops for American students. He spent the better part of 1938 with the Republican Army in Spain fighting against Francisco Franco’s fascist dictatorship before returning to Mexico City to work on a project for the electrician’s union. In a stairwell of the Sindicato Mexicano de Electricistas, Siqueiros designed one of his most famous works, Portrait of the Bourgeoisie, warning against the duel foes of capitalism and fascism. The piece shows these two forces operating as a single political machine, swallowing workers to create wealth. Yet an armed, brave-faced revolutionary, of unnamable class or ethnicity, dives into the scene to rescue the workers, and a blue sky on the ceiling flanked by electrical towers displays hope for the proletariat in technological and industrial advances. Before the mural’s completion in 1940, however, Siqueiros was forced into hiding and later jailed for his links to an attempt to assassinate Leon Trotsky, then in exile in Mexico City from the Soviet Union.

Siqueiros participated in the first ever Mexican contingent at the XXV Venice Biennale exhibition with Orozco, Rivera and Tamayo in 1950, and he received the second prize for all exhibitors, which recognized the international status of Mexican art. Yet by the 1950s, Siqueiros returned to accepting commissions from what he considered a “progressive” Mexican state, rather than painting for galleries or private patrons. He painted an outdoor mural entitled The People to the University, the University to the People at the National Autonomous University of Mexico in Mexico City in 1952. In 1957 he began work on a 4,500-square-foot (420 m²) government commission for Chapultepec Castle in Mexico City; Del porfirismo a la Revolución was his biggest mural yet. (The painting is known in English as From the Dictatorship of Porfirio Diaz to the Revolution or The Revolution Against the Porfirian Dictatorship.)

In the lobby of the Hospital de la Raza in Mexico City, he created a revolutionary multi-angular mural using new materials and techniques, "For the Social Welfare of all Mexicans." After painting "Man the Master and Not the Slave of Technology" on a concave aluminum panel in the lobby of the Polytechnic Institute, he painted "The Apology for the Future Victory of Science over Cancer" on panels which wrap around the lobby of cancer center.

Yet near the end of the decade, his outspoken political ideas and activities alienated him from the government as well as the general public. Under pressure from the government, the National Actors’ Association, which had commissioned a mural on the theater in Mexico suspended his work on The History of Theater in Mexico at the Jorge Negrete Theater and sued him for breach of contract in 1958.

Siqueiros was eventually arrested in 1960 for openly attacking the President of Mexico and leading protests against the arrests of striking workers and teachers, though the charges were commonly known to be false. Numerous protests ensued, even including an appeal by well-known artists and writers in a New York Times ad in 1961. Unjustly imprisoned, Siqueiros continued to paint, and his works continued to sell. During that stay, he would make numerous sketches for the project of decorating the Hotel Casino de la Selva, owned by Manuel Suarez y Suarez. Siqueiros was finally released in spring of 1964 and immediately resumed work on his suspended murals in the Actors' Union and Chapultepec Castle.

When the mural planned for the Hotel de la Selva in Cuernavaca was moved to Mexico City and expanded, he assembled a team of national and international artists to work on the panels in his workshop in Cuernavaca. This project, his last major mural, is the largest mural ever painted, an integrated structure combining architecture, in which the building was designed as a mural, with mural painting and polychromed sculpture. Known as the Polyforum Siqueiros, the exterior consists of 12 panels of sculpture and painting while the walls and ceiling of the interior are covered with "The March of Humanity on Earth and Toward the Cosmos." Completed in 1971 after years of extension and delay, the mural broke from some previous stylistic mandates, if only by its complex message. Known for making art that was easily read by the public, especially the lower classes, Siqueiros message in The March is more difficult to decipher, though it seems to fuse two visions of human progress, one international and one based in Mexican heritage. The mural’s placement at a ritzy hotel and commission by its millionaire owner also seems to challenge Siqueiros’ anti-capitalist ideology.

As a muralist, and an artist Siqueiros believed art should be public, educational, and ideological. He painted mostly murals and other portraits of the revolution – its goals, its past, and the current oppression of the working classes. Because he was painting a story of human struggle to overcome authoritarian, capitalist rule, he painted the everyday people ideally involved in this struggle. Though his pieces sometimes include landscapes or figures of Mexican history and mythology, these elements often appear as mere accessories to the story of a revolutionary hero or heroes (several works depict the revolutionary "masses," such as the mural at Chapultepec). His interest in the human form developed at the Academy in Mexico City. His accentuation of the angles of the body, its muscles and joints, can be seen throughout his career in his portrayal of the strong revolutionary body. In addition, many works, especially in the 1930s, prominently feature hands, which could be interpreted as another heroic symbol of proletarian strength through work: his self portrait in prison (El Coronelazo, 1945, Museum of Modern Art, Mexico City), Our Present Image (1947, Museum of Modern Art, Mexico), New Democracy (1944, Palace of Fine Arts, Mexico City), and even his series on working class women, such as The Sob.