He was born Lafayette Maynard Dixon in Fresno, California, named after his maternal grandfather. His family of aristocratic Virginia Confederates had found a new home in California after the American Civil War. His father was Henry "Harry" St. John Dixon a former Confederate officer turned rancher. His mother, Constance Maynard, a well-educated daughter of a Navy officer from San Francisco, shared her love of classic literature with the young boy and encouraged him in his writing and drawing. His brother Harry St. John Dixon  was a metalsmith.

Dixon moved to San Francisco in 1893 and studied with Arthur Mathews at the California School of Design (now San Francisco Art Institute). There he became a friend of Tonalist painter Xavier Martinez, with whom he traveled to Monterey, Carmel, and Point Lobos.

In 1900 Dixon visited Arizona and Mexico, later accompanied artist Edward Borein on a horseback trip through several western states. Also he arranged for the debut exhibition of the soon-to-be-famous sculptor Arthur Putnam in the “jinks room” of the San Francisco Press Club. Dixon's sketching trip through Arizona and Guadalajara in March and April 1905 with Martinez garnered much attention in the press. Dixon moved into Martinez's Montgomery Street atelier; their joint studio exhibitions were usually held on Saturdays. To insure a steady income, he worked as an illustrator for local newspapers and magazines (including the Overland Monthly and Sunset magazine), and illustrated numerous books, such as Clarence E. Mulford’s Hopalong Cassidy.

For his first exhibition in the southwest, Dixon contributed four oils to the show of Modern Art From The American West curated by the well-known impressionist Jennie V. Cannon at the University of Arizona in Tucson in December of 1912.

In 1917, to support America’s entry into World War I, Dixon joined Lee F. Randolph, Bruce Nelson, and other artists on a committee to redesign U.S. Army camouflage.

During his tenure in northern California, he was a prolific contributor to art exhibitions. His first publicized exhibition was a show of “regional artists” in Alameda, California during the spring of 1899. Thereafter he exhibited at major venue: California Society of Artists (1902); Bohemian Club (1903–1928); San Francisco Art Association (1903–1931); Newspaper Artists League (1903); Press Club (1904); Hotel Del Monte Art Gallery (1907–1909); Panama–Pacific International Exposition (1915); Gump's Gallery (1920 – solo exhibition); San Francisco Print Rooms (1920 – this show was later sent to Honolulu); San Francisco's Don Lee Galleries (1923); Oakland Art Gallery (1926–1928); University of California, Berkeley (1928); California State Fair (1928); and Golden Gate International Exposition (1939).^[Between 1925 and 1933, art dealer Beatrice Judd Ryan ran the Galerie Beaux Arts in San Francisco, with guidance from Dixon. The Galerie Beaux Arts was the first contemporary gallery in the city, as well as a cooperative nonprofit, which supported local modern artists.

In 1926, Dixon was co-curator with Laura Adams Armer for an exhibit of “Pueblo and Navajo Arts & Crafts” at the Paul Elder Gallery of San Francisco under the auspices of the Indian Defense Association of Central and Northern California. In 1927 he joined several prominent artists in a boycott of the Bohemian Club Annual Exhibition when works of the more “modern” artists were excluded. During February 1930 he was one of a handful of artists, which included Ralph Stackpole, Otis Oldfield, Helen Katharine Forbes, and several others, who contributed to a Galerie Beaux Arts show where the subject of every painting was the same female model. During the summer of 1931 he exhibited with the most prominent artists of the west, including William Ritschel, Armin Hansen, Granville Redmond, and Leland Curtis, at the Tahoe Tavern on Lake Tahoe. Between 1935 and 1943 he was a member of the Society of the Thirteen Watercolorists that exhibited at the: San Francisco Museum of Art, California Palace of the Legion of Honor (museum), Stanford University Art Gallery; and the de Young Museum.

For a time, he lived in New York with his young wife and baby daughter Constance, but soon returned to the western United States where he said he could create "honest art of the west" instead of the romanticized versions he was being paid to create. Shortly after he began a new life in San Francisco, his first marriage ended.

Dixon developed his style during this period, and western themes became a trademark for him. In San Francisco, Dixon was considered a colorful character with a good sense of humor.  He often dressed like a cowboy and seemed determined to impart a western style, most often in the form of a black Stetson hat, boots, and a bola tie.

Influenced in part by the Panama Pacific International Exposition of 1915, Dixon began to search for a new expression, moving away from impressionism and into a simpler, more modern style. Meeting and marrying Dorothea Lange, a portrait photographer from the east, had a great influence on his art. They married in 1920 and by 1925, the year their first son Daniel Rhodes Dixon was born (15 May), Maynard's style had changed dramatically to even more powerful compositions, with the emphasis on design, color, and self-expression. A true modernist emerged. The power of low horizons and marching cloud formations, simplified, and distilled, became his own brand and at once were both bold and mysterious. On 12 June 1928, their second son was born, John Eaglefeather Dixon.

During the Great Depression, Dixon painted a series of social realism canvases depicting the prevailing politics of maritime strikes, displaced workers, and those affected by the depression. Simultaneously, Lange captured on film images of the migrant workers in the Salinas Valley and the city breadlines, images that eventually brought her fame. In 1933 the Dixons spent the summer in Zion National Park with sojourns to the hamlet of Mount Carmel, Utah. Lange was called back to San Francisco, a separation that led to the couple's divorce in 1935.

Two years later, Dixon married San Francisco muralist Edith Hamlin. The couple left San Francisco two years later for southern Utah, the source of some of Dixon's greatest art. In 1939, the couple built a summer home in Mount Carmel, where Dixon found new friends and became reacquainted with the local natural landscapes. He lived near the cottonwood trees along an old irrigation ditch and took short hikes to a plateau where he loved the quiet. Dixon spent winter months in Tucson, where the couple also had a home and studio.

Dixon continued to create simple but powerful compositions in which non-essential elements were distilled or eliminated. In 1946, Maynard died at his home in Tucson. In the spring of 1947, his widow Edith brought his ashes to Mount Carmel where she buried them on a high bluff above the art studio being built on the property. This had been at his request and she felt it a fitting tribute where friends could come to pay respects and view the land that he loved.

In addition to painting, he also wrote poetry. An article in the California Historical Quarterly described his poetry as "very competent and sometimes superb".

The largest collection of Dixon's works is at Brigham Young University, at the Museum of Art.

There are two museums devoted to Dixon and his works. The Maynard and Edith Hamlin Dixon House and Studio, operated by the Thunderbird Foundation, offers guided tours at Mount Carmel, Utah. The foundation is working to establish a separate museum and regional art center that would feature works by Maynard Dixon and his circle, Milford Zornes and his circle, as well as contemporary work by local artists.

There is a Maynard Dixon Museum inside the Mark Sublette Medicine Man Gallery in Tucson, Arizona. Works by Dixon include paintings, watercolors, pastels, drawings, poetry, and illustrations.

The full-length documentary film, Maynard Dixon: Art and Spirit (2007) was directed by Jayne McKay, and includes candid commentary from their children and extended family. The television program, Maynard Dixon: To the Desert Again (2007), was produced by KUED-TV.