Duke was born in New York City, the only child of tobacco and hydroelectric power tycoon James Buchanan Duke and his second wife, Nanaline Holt Inman, widow of Dr. William Patterson Inman. At his death in 1925, the elder Duke's will bequeathed the majority of his estate to his wife and daughter, along with $17 million in two separate clauses of the will, to The Duke Endowment he had created in 1924. The total value of the estate was not disclosed, but was estimated variously at $60 million to $100 million (equivalent to $837 million to $1.395 billion in 2018), the majority culled from J.B. Duke's holds in Lucky Strike cigarettes. Duke spent her early childhood at Duke Farms, her father's 2,700-acre (11 km2) estate in Hillsborough Township, New Jersey.

Duke's first major philanthropic act was to establish Independent Aid, Inc., in 1934, when she was 21 years old, in order to manage the many requests for financial assistance addressed to her. In 1958, she established the Duke Gardens Foundation to endow the public display gardens she started to create at Duke Farms. Her Foundation intended that Duke Gardens "reveal the interests and philanthropic aspirations of the Duke family, as well as an appreciation for other cultures and a yearning for global understanding.". Duke Gardens were the center of a controversy over the decision by the trustees of the Doris Duke Charitable Foundation to close them on May 25, 2008.  In 1968, Duke created the Newport Restoration Foundation with the goal of preserving more than eighty colonial buildings in the town. Historic properties include Rough Point, Samuel Whitehorne House, Prescott Farm, the Buloid-Perry House, the King's Arms Tavern, the Baptist Meetinghouse, and the Cotton House. Seventy-one buildings are rented to tenants. Only five function as museums. She also funded the construction of Maharishi Mahesh Yogi's ashram in India, visited by the Beatles in 1968.  Duke's extensive travels led to an interest in a variety of cultures, and during her lifetime she amassed a considerable collection of Islamic and Southeast Asian art. After her death, numerous pieces were donated to The Asian Art Museum of San Francisco and the Walters Art Museum of Baltimore.  Duke did much additional philanthropic work and was a major benefactor of medical research and child welfare programs. In the late 1980s, Duke donated $2 million to Duke University to be used for AIDS research. Her foundation, Independent Aid, became the Doris Duke Foundation, which still exists as a private grant-making entity. After her death, the Doris Duke Charitable Foundation was established in 1996, supporting four national grant making programs and Doris Duke's three estates, Shangri La, Rough Point, and Duke Farms.

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