Educated at McGill University School of Architecture in Montreal, Safdie began his career (1962) in the offices of Philadelphia architect Louis I. Kahn. He subsequently opened his own architectural offices in Montreal, Jerusalem, and Boston. Early works by Safdie include Habitat Puerto Rico (1968–72), a modular housing system in San Juan; Yeshivat Porat Joseph Rabbinical College, with dormitories, teaching facilities, library, and synagogue, in Jerusalem (1971–79); Coldspring New Town, commissioned by the city of Baltimore, a plan for a new town, including residences and related public and service buildings (1971); and Wailing Wall Plaza, in the Old City, Jerusalem (1974). Safdie became professor of urban design and director of the urban design centre of the Harvard University Graduate School of Design in 1978.

His later projects include, at Yad Vashem in Jerusalem, a children's Holocaust memorial (completed 1987), a transport memorial (completed 1995), and a Holocaust museum (completed 2005)—as well as the Telfair Museum of Art (completed 2006) in Savannah, Ga., U.S., and an expansion of the Lester B. Pearson Airport in Toronto, Ont., Can. With offices in Boston, Jerusalem, and Toronto in the early 21st century, Safdie had projects in Israel, China, the United States, Singapore, and Bangladesh.