Born in London, Ontario, Holmes attended the University of Western Ontario and received a Master of Arts degree from the University of Toronto. From 1933 to 1938, he was a master of English at Pickering College. From 1938 to 1940, he attended the University of London. He joined the Department of External Affairs in 1943 as a temporary wartime assistant.
From 1947 to 1948, he was the Canadian Chargé d'Affaires ad interim to the Soviet Union. In 1950, he was appointed Acting Permanent Delegate to the United Nations. He became Assistant Under-Secretary of State for External Affairs in 1953 where he remained until his retirement in 1960. From 1960 to 1973, he the president (later called director-general) of the Canadian Institute of International Affairs, a non-partisan, non-profit, and non-governmental organization for the discussion and analysis of international affairs.
From 1971 to 1981, he was a Professor of International Relations at York University, Glendon College. From 1967 until his death, he was a Visiting Professor of International Relations at the University of Toronto. He was also a Visiting Professor of History at the University of Leeds in 1979 and 1985.
He was the author of Life with Uncle: the Canadian-American Relationship (1981) and The Shaping of Peace: Canada and the Search for World Order 1943-1957 (2 volumes, 1979 and 1982). In 1986, he was awarded the Royal Society of Canada's J. B. Tyrrell Historical Medal in recognition of these volumes.
In 1969, he was made an Officer of the Order of Canada. He was a Fellow of the Royal Society of Canada and the recipient of 10 honorary doctorates.