Charles Demuth was born November 8, 1883 in Lancaster, Pennsylvania. He graduated from Franklin & Marshall Academy before studying at Drexel University and at Philadelphia's Pennsylvania Academy of Fine Arts. While he was a student at PAFA, he met William Carlos Williams at his boarding house. The two were fast friends and remained close for the rest of their lives.
He later studied at Académie Colarossi and Académie Julian in Paris, where he became a part of the avant garde art scene. The Parisian artistic community was accepting of Demuth's homosexuality.
While he was in Paris he met Marsden Hartley by walking up to a table of American artists and asking if he could join them. He had a great sense of humor, rich in double entendres and they asked him to be a regular member of their group. Through Hartley he met Alfred Stieglitz and became a member of the Stieglitz group. In 1926, he had a one-man show at the Anderson Galleries and Intimate Gallery the New York gallery run by his friend Alfred Stieglitz.
His most famous painting, I saw the Figure 5 in Gold, was inspired by his friend William Carlos Williams's poem The Great Figure. According to Roberta Smith of the New York Times "Demuth's famous visionary accounting of Williams, I Saw the Figure Five in Gold, a painting whose title and medallion-like arrangement of angled forms were both inspired by a verse the poet wrote after watching a fire engine streak past him on a rainy Manhattan street while waiting for Marsden Hartley, whose studio he was visiting, to answer his door."  This is one of nine poster portraits Demuth created to honor his creative friends. He painted poster portraits for artists Georgia O'Keeffe, Arthur Dove, Charles Duncan, Marsden Hartley, John Marin and for the writers Gertrude Stein, Eugene O'Neill, Wallace Stevens and Williams.
In 1927, Demuth started a series of seven panel paintings depicting factory buildings in his hometown. He finished the last of the seven, After All in 1933, and died two years later. Six of those paintings are highlighted in Chimneys and Towers: Charles Demuth’s Late Paintings of Lancaster, a 2007 Amon Carter Museum retrospective of his work, displayed in 2008 at the Whitney Museum of American Art.
According to the exhibit notes from the Amon Carter show, Demuth's will left many of his paintings to his friend Georgia O'Keeffe. Her strategic decisions regarding which museums received these works cemented his reputation as a major painter of the Precisionist school.
Demuth suffered either an injury when he was four years old or may have had polio or tuberculosis of the hip that left him with a marked limp and required him to use a cane. He later developed diabetes and was one of the first people in the United States to receive insulin. He spent most of his life in frail health, and he died in Lancaster on October 23, 1935, at the age 51, of complications from diabetes.