Charles Henry Buckius Demuth was both on November 8, 1883, on 109 North Lime Street in Lancaster, Pennsylvania. He was the only child of Ferdinand and Augusta Demuth. The Demuth family established the oldest continuing tobacco shop and snuff factory in America. His family's tobacco shop was such a success that Demuth never had to work as a teenager. Demuth's grandfather, Charles Buckius was also very well-known in Lancaster because he was the superintendent of the shoe department at the Lancaster County prison and he owned fourteen lower income rental properties in Lancaster County.

At the age of five, Demuth developed a hip illness, later known as Perthes, a common hip disease boys of that time developed at that age. Due to his chronic hip problem as a young boy, Demuth became very introverted and very close to his mother, Augusta. He tended to always play with the girls in grade school because his mother and aunt believed that the boys at school would play too rough and cause his hip injury to worsen. When Demuth was bedridden, his mother gave him crayons and watercolors, which was the beginning of his love for art. Demuth's parents did not try to stop him from pursuing his love for art at such a young age because they knew he was ill and they wanted him to do what he enjoyed, although his father always hoped that Demuth would continue on with the family tobacco company. His father, Ferdinand, was an amateur photographer and both his grandmother and aunt were painters. After his hip injury began to heal and he was no longer bedridden, his mother sent him to Martha Bowman for private art lessons in still-life and landscape painting.

Demuth's earliest works consisted of china teacups, saucers, and plates with flowers and Chinese dragons painted on them. He tended to create a lot of Chinese influenced works, which was very unusual for a teenage boy. Much of his feminine paintings and artistic techniques were attributed to the constant time he spent with his mother and other female figures in his life. At the age of sixteen, he enrolled in Franklin and Marshall Academy, a prestigious boys preparatory school in Lancaster. His concentration at the academy was known as the "scientific track," which consisted of math and other subjects to prepare him for the business world, mostly because his father wanted him to continue on with the family tobacco business. After receiving average math and science scores and superior grades in English, history, and language, his family finally realized that his true interest was in art. Demuth graduated from Franklin and Marshall Academy in June of 1901, and after that he lived at home for the next two years until October of 1903 when he enrolled in Drexel Institute of Art, Science, and Industry in Philadelphia.

Howard Pyle, the founder of Drexel Institute inspired Demuth to focus much of his early artistic works on the topics of illustration field and graphic producing. During the summer of 1904, Demuth studied at the Pennsylvania School of Industrial Art so that he could catch up on some summer art classes. Upon returning to Drexel in September of 1904, he had improved his artistic abilities so much that he was able to skip several art classes and continue on with more advanced classes at the institute. By the end of the term at Drexel, Demuth earned two awards, second place in antique drawing and honorable mention in illustration composition. In June 1905, Drexel stated that they were eliminating their fine and applied arts program and because of this Demuth decided to attend the Pennsylvania Academy of Fine Arts.

During his time at the Academy, he traveled to Paris to study some French works of art and returned home to graduate from the Academy in 1910. After graduating from the Academy, he returned to Paris once again to continue painting and using inspiration from the city throughout his works of art. He even continued studying in Paris at the Academie Moderne, Academie Collars, and the Academie Julieun. After returning from Paris, Charles split up most of his time living in either Lancaster or New York. He often created many of his paintings and based many of his works of art on different aspects of Lancaster County, and he would travel to New York to enter his works into different contests or galleries. Demuth is said to have continued to stay in Lancaster because this is where his mother resided and she was an inspiration for many of his artistic works. In 1914, he had his first man show at Daniel Gallery in New York. Demuth also served on several committees and was responsible for organizing the Loan Exhibition of Historical and Contemporary Portraits Illustrating the Evolution of Portraiture of Lancaster County. In this exhibition Demuth contributed Self-Portrait, which was the only work he ever exhibited during his lifetime. Andrew Ritchie wrote in his book Charles Demuth that during the year of 1915 Demuth "began to produce a stream of increasingly beautiful work." The peak of Demuth's career was from 1915-1920, and during this time he created poster portraits to honor many of his friends. He also created many fruit still-lifes in watercolor during this time. Demuth was inspired by other countries, especially France because he traveled there so often, and he would often incorporate what he saw into his own style. During the summers of 1915 and 1916, he spent much of his time in Provincetown, Massachusetts, with fellow friends and painters. Demuth used many of the houses in Provincetown in his paintings. In 1919, he was chosen by the Pennsylvania Academy of Fine Arts to serve as a member on the jury of selection and award their annual exhibition of watercolors.

Demuth never decided to marry and because of this many people thought he was a homosexual, but little is actually known about Demuth's love life. In the book, Homage to Charles Demuth, Thomas Norton writes that Demuth was often referred to as a "shadowy figure" because so little was known about the middle years of his life. A friend of Demuth's, Susan Street, states in the book Homage to Charles Demuth, that "Demuth did not associate with many people in Lancaster. He would shut himself off." Demuth was most recognized as an American still life painter, but he incorporated many other disciplines into his art including illustrative, floral, and landscape paintings. In 1920, Demuth was diagnosed with diabetes and his intense symptoms slowed down his production of paintings. Demuth was among one of the first people in America to give himself injections of insulin to help control his diabetes. Despite his illness he continued painting and in 1920 he created a series of architectural paintings of buildings in Lancaster. In 1925, he started working with Alfred Stieglitz, a well-known photographer, who was married to Georgia O'Keeffe, another well-known artist. Throughout his time working with Stieglitz, he continued to stay in Lancaster and paint still-lifes with major oils and continued using his architectural style in his paintings.

On October 23, 1935, Charles Demuth died of diabetes. His death occurred 15 days before his 52nd birthday. He was buried in the Demuth plot in Lancaster Cemetery in a wide-tree shaded section. In his will he bestowed his oils to Georgia O'Keeffe and today many of these oils can be found in American museums. One of his last major works was created in 1931 and was titled And the Home of the Brave and his last series of works consisted of watercolor beaches of Provincetown. A memorial exhibition was created at the Whitney Museum of American Art in New York in late 1937 and a retrospective was created at the Museum of Modern Art in 1950. During his life time he created over nine-hundred different works of art.

Charles Demuth was most famous for his still lifes and much of his life still remains a mystery because so little was known about the working part of his life. Thomas Norton states that Demuth "left no family, no money, and no memoirs and one must allow his paintings to tell us what they can." Marcel Duchamp, a friend of Demuth's and a very famous painter from Paris, stated that "it was fun to be with Demuth, because he did not care where he belonged or where he was on the social scale, and he was an artist worthy of the name, without the pettiness which afflicts most artists, worshipping his inner self without the usual eagerness to be right." Betsy Fahlman refers to Demuth in her book, Pennsylvania Modern: Charles Demuth of Lancaster, as "an individual that created a lot of enthusiasm for and keen understanding of the most advanced developments of American and European art. He was regarded as the most important figure in contemporary American paintings."