Edward Durell Stone was born in Fayetteville, Arkansas, in 1902 and received his early education there. He followed his brother Hicks Stone to Boston, where in 1926 he received a Harvard scholarship and began his studies in architecture. He transferred to the Massachusetts Institute of Technology a year later. In 1927 he was awarded a Rotch Traveling Scholarship that supported his study of architecture in Europe for two years. When he returned to the United States he joined a firm of architects in New York City.

He designed several residential projects in the newly recognized International Style in the 1930s. The Richard H. Mandel house in Mount Kisco, New York, designed in 1934, was described by Stone as "the first modern house in the East." The concrete and steel construction, strip windows and glass block were also used in the A. Conger Goodyear house on Long Island and the Ulrich Kowalski house in Mount Kisco. The Museum of Modern Art, designed in 1937 in collaboration with Philip Goodwin, was the first major building in the International Style in New York City. In 1937 Stone received the Silver Medal of the Architectural League for the South Carolina residence of Mr. and Mrs. Henry R. Luce, which required its own modern power plant and utilities but also incorporated details reflecting the ante-bellum Charleston Tradition.

In the 1940s and 1950s, Stone moved away from the Internationalist aesthetic, developing his own style that combined the grace and elegance of the classical traditions with contemporary materials and methods. He designed many important government and business structures. El Panama Hotel in 1946 set the style for resort hotels around the world. The United States Embassy in New Delhi, 1954, brought him international recognition. Other government projects included the United States pavilion at the 1958 World's Fair in Brussels, and the Kennedy Center for the Performing Arts in Washington, originally designed in 1958. His corporate projects included buildings for Pepsico, General Motors, Standard Oil, and the National Geographic Society. He also designed educational structures, including the entire campuses of the University of Arkansas Medical Center, Harvey Mudd College, the University of Islamabad, and the State University of New York at Albany.

Stone received many professional honors in his career, many of which extended to the international level, especially during the 1950s and 1960s. In 1952 the Architectural League awarded him the Gold Medal of Honor for El Panama Hotel. In 1967 he received the American Institute of Architects Honor Award for the Ponce Museum in Puerto Rico. During the construction of the Brussels World's Fair pavilion, he was the subject of a cover story in Time. In 1962 Stone published his memoir, Evolution of an Architect. A second book, Recent and Future Architecture, was published in 1967.