After studying at the University of Illinois, Urbana, Griffin worked in Frank Lloyd Wright's architectural studio at Oak Park, Ill., in the first decade of the 20th century. There he met the architect-renderer Marion Mahony, whom he married in 1911 and who took an active part in his practice. Among his early independent commissions were the William H. Emery House, Elmhurst, Ill. (1902), influenced by Wright's Prairie houses, and the landscaping of the campus of Northern Illinois State Teachers' College (afterward University), DeKalb (1906). He laid out the Rock Glen residential development, Mason City, Iowa (1910–16), and designed several of its houses.

Early in 1912 Griffin won an international competition to plan Canberra, the new federal capital of Australia, and he spent most of the rest of his life in that country. Starting with the “Garden City” ideal of strict separation of functions within a community, he adopted a geometric formalism. The main streets of the city were to radiate from focuses—the houses of Parliament, a municipal centre, and a commercial district. From 1915 Griffin was in charge of construction, but in 1920, following a dispute with Prime Minister William Morris Hughes, he lost control of the project. Other works by Griffin in Australia include Newman College, University of Melbourne (1915), and the Castlecrag residential community, Sydney (1918).