He was born in Maywood, in Chicago, Illinois. He obtained a degree in architecture in 1899.
From 1901 to 1912, he worked for Frank Lloyd Wright in Oak Park, Illinois. During this time, he designed many houses in the Chicago area. He also married Maria Lucy Mahoney in 1911.
In 1911, he won the design competition for Australia's new capital Canberra. In 1914, he and his wife moved to Australia, where they stayed for the next 21 years.
He oversaw the design of North and South Canberra during this time, though he had to struggle with politics and bureaucracy. Several parts of his basic design underwent change. For instance, plans to create a Westbourne, Southbourne and Eastbourne Avenue to complement Canberra's Northbourne Avenue came to nothing. An intended series of streets arranged in asterisk fashion intended for inner south-east Canberra (in what are now the suburbs of Fyshwick and Narrabundah) were similarly never built.
He later designed the inner northern Sydney suburb of Castlecrag. It used what was at that time the novel concept of including native bushland in the design. He also helped to design the New South Wales towns of Leeton and Griffith.
In 1935 the Burley-Griffins left Australia to go to Lucknow, India. During his time there, he designed a series of 60 university buildings. This activity ceased in 1937, when he died from peritonitis, following an unsuccessful operation.
A landmark in Chicago and an artificial lake in Canberra are both named after him.