He was named Hakadah at his birth on a reservation near Redwood Falls, Minnesota. In Dakota, Hakadah means the "pitiful last", as his mother Mary died at his birth. He was later named Ohíye S’a (Dakota for "wins often") after winning a rough game of lacrosse.. He was the son of Wak-anhdi Ota (Many Lightnings) and his mixed-race wife, Wakhá?tha?kawi? (Goddess), a.k.a. Winona (first-born daughter) and Mary Nancy Eastman.

Mary was the daughter of the American painter and military officer, Seth Eastman, and Wakhá? Iná?i? Wi? (Stands Sacred). Stands Sacred was the daughter of Cloud Man, a Dakota (Santee Sioux) chief. Seth Eastman, born in New England, was stationed as a captain in the US Army at Fort Snelling in present-day Minnesota when he and Wakhá? Iná?i? Wi? had their daughter.

Ohíye S’a was the youngest of five children, with three older brothers (John, David, and James) and an older sister Mary. During the Minnesota Uprising of the Dakota in 1862-63, Ohíye S’a was separated from his father. He was cared for by paternal relatives who took him into North Dakota and Manitoba, Canada. Later he was reunited with his father and older brother John in South Dakota. The father had by then taken the surname Eastman and called himself Jacob, after converting to Christianity. The Eastman family established a homestead in Dakota Territory. Like his father and brother, Ohíye S’a accepted Christianity; he then took the name Charles Alexander Eastman.

With his father's strong support for education, Eastman and his older brother John attended mission, preparatory schools, and college. Eastman first attended Beloit College and Knox College; he graduated from Dartmouth College in 1887. He went on to medical school at Boston University, where he graduated in 1889.

His older brother became a minister. Rev. John (Ma?piyawaku Kida) Eastman was a Presbyterian missionary at Flandreau, South Dakota.

Charles Eastman worked as agency physician for the Bureau of Indian Affairs (BIA) Indian Health Service on the Pine Ridge Reservation and later at the Crow Creek Reservation, both in South Dakota. He cared for Indians after the Wounded Knee massacre. He also established a private medical practice.

Between 1894-98, Eastman established 32 Indian groups of the Young Men's Christian Association (YMCA) and established leadership programs and outdoor youth camps. In 1899, he helped recruit students for the Carlisle Indian Industrial School in Pennsylvania. In 1902 Eastman published a memoir, Indian Boyhood, recounting his first fifteen years of life among the Sioux during the waning years of the nineteenth century. In the following years, he wrote a total of eleven books, most concerned with his Native American heritage. They enjoy regular reprints, and some books have been translated into French, German and other European languages. A selection of his writings was published recently as The Essential Charles Eastman (2007).

Inspired by his writings, Ernest Thompson Seton sought his counsel in forming his popular group for boys, the Woodcraft Indians. The New York YMCA then asked both Seton and Eastman to help them design the YMCA Indian Scouts for urban boys, using rooftop gardens and city parks for their activities. Because of this work, in 1910, Eastman was invited to work with Ernest Thompson Seton, founder of the Woodcraft Indians, and Daniel Carter Beard of the Sons of Daniel Boone, to help found the Boy Scouts of America. Luther Gulick also depended heavily on Eastman to assist he and his wife Charlotte Vetter Gulick in the creation of the Camp Fire Girls.

Eastman used his fame as an author and lecturer to promote the fledgling Boy Scouts and Camp Fire Girls, and advised them on how structure their summer camps, even running one of the first Boy Scout camps along the shores of the Chesapeake Bay, and his daughter Irene working as a counselor at one of the Pittsburgh Camp Fire Girl camps. His family soon ran their own camps and he served as a BSA national councilman for many years. In 1911, Eastman was chosen to represent the American Indian at the Universal Races Congress in London. Throughout his speeches and teachings, he emphasized peace and living in harmony with nature.

Eastman was active in national politics, particularly in matters dealing with Indian rights. He served as a lobbyist (sometimes taking on attorney-like responsibilities to plead their cases) for the Dakota between 1894 and 1897. In 1903, President Theodore Roosevelt assigned Eastman to help members of the Sioux nations (Dakota, Nakota, Lakota) to choose English legal names to prevent individuals and families from losing their allotted lands because of confusion over names. Eastman was one of the co-founders of the Society of American Indian (SAI), which pushed for Freedom and Self Determination for the Indian. From 1923-25, Eastman served as an Indian inspector under President Calvin Coolidge.

He was also invited by the administration to serve as a member of the Committee of One Hundred, a reform panel examining federal institutions and activities dealing with Indian nations. This committee recommended an in-depth investigation into reservation life (health, education, economics, justice, civil rights, etc.), which resulted in the groundbreaking Meriam Report. The findings and recommendations served as the basis of the Roosevelt Administration's New Deal for the Indian, which sought none other than freedom and self determination for the Indians.

In 1925, the Bureau of Indian Affairs asked Eastman to investigate the death and burial location of Sacagawea, the woman who guided and interpreted for the Lewis and Clark Expedition in 1805. He determined that she died of old age at the Wind River Indian Reservation in Wyoming on April 9, 1884. More recently because of records discovered, historians believe that she died in 1812 as a result of an illness following childbirth at Fort Manuel Lisa in what became North Dakota.

In 1933, he was selected from among many candidates to receive the first American Indian Achievement Award. His work with youth and public speaking continued for the remainder of his life.

In 1891, Eastman married the poet and Indian welfare activist Elaine Goodale, who served briefly as superintendent of Indian boarding schools in the Dakota Territory. They had six children together. The marriage prospered at first, but Eastman's many jobs, financial pressures, and absences on the lecture circuit, which left his wife to parent their children alone, put increasing strain on the marriage. They separated about 1920, following the death of their daughter Irene.

Her latest biographer believes that cultural differences also contributed the breakdown of the marriage. Others have suggested their differing views on assimilation. Goodale believed the Indians must totally assimilate. Eastman believed that they could retain strong elements from their culture and still participate fully and contribute to American life. Elaine Goodale Eastman died in 1953.

Charles Eastman built a cabin on the eastern shore of Lake Huron where he spent his later-year summers. He wintered in Detroit with one of his sons where he died January 8, 1939 of a heart attack at the age of 80, and was buried in an unmarked grave.

As a child, Ohiyesa had learned about herbal medicine from his grandmother. Going to medical school enabled him to draw from both sides of his heritage in becoming a doctor.

In 1933, Eastman was the first to receive the Indian Achievement Award.

Film portrayal

In the HBO film Bury My Heart at Wounded Knee (2007), Eastman was portrayed by the actors Adam Beach and Chevez Ezaneh.