She was born Anna Mary Robertson in Greenwich, New York. She spent most of her life as a farmer's wife and the mother of five children. She married Thomas Salmon Moses in 1887. They lived in the Shenandoah Valley, then later settling at Eagle Bridge.

She began painting in her seventies after abandoning a career in embroidery because of arthritis.

Her artwork was discovered by Louis J. Caldor, a collector who noticed her paintings in a Hoosick Falls, New York drugstore window in 1938. In 1939 an art dealer named Otto Kallir exhibited some of her work at his Galerie Saint-Etienne in New York City. This brought her to the attention of art collectors all over the world, and her paintings were highly sought after. She went on to have exhibitions of her work throughout Europe and even in Japan, where her work was particularly well received. She continued her prolific output of paintings, the demand for which never diminished during her lifetime.

President Harry S. Truman presented her with the Women's National Press Club Award for outstanding accomplishment in art in 1949. In 1951, she appeared on See It Now, a television program hosted by Edward R. Murrow.

Grandma Moses painted mostly scenes of rural life. Some of her many paintings were used on the covers of Hallmark cards, making the paintings timeless classics.

"Grandma" Moses celebrated her 100th birthday on the 7th of September, 1960. New York governor Nelson Rockefeller proclaimed the day "Grandma Moses Day" in her honor. Her gravestone is inscribed with this epitaph: "Her primitive paintings captured the spirit and preserved the scene of a vanishing countryside." She had outlived most of her children.

She died at Hoosick Falls on December 13, 1961 and is buried at the Maple Grove Cemetery.