After the start of the Axis occupation of Greece in 1941 he founded the Omiros resistance group, and in 1942 he fled to the Middle East, where he served as Minister of Defence under the Tsouderos government in exile during World War II.

He also served in other ministerial posts under Alexandros Diomidis, Constantine Karamanlis and others till 1967 when he became prime minister.

On 9 July 1961 Panagiotis Kanellopoulos as Deputy Prime Minister in Konstantinos Karamanlis' government and German Vice-Chancellor Ludwig Erhard signed the protocols of Greece's Treaty of Association with the European Economic Community (EEC).

The signing ceremony in Athens was attended by top government officials from the six-member group consisting of Germany, France, Italy, Belgium, Luxemburg and the Netherlands.

He was the last Prime Minister (acting as a caretaker for the scheduled for 28 May) prior to the coup d'état of 21 April 1967.