He studied philology at the Faculty of Philosophy of the University of Athens. He then specialized in archaeology in Germany. He returned and was appointed curator of antiquities (1885). Later he became a lecturer in archaeology at the University of Athens. He conducted excavations in Laconia and Messinia.
In 1900 he resigned to begin his political career in Samos. He formed his own political group with the aim of the autonomy of the State of Samos, denouncing the mismanagement of the Christian rulers appointed by the Gate and calling for the expansion of political freedoms. The ruler of Chios, Andreas Kopasis went so far as to ask the Sultan for military reinforcements! The Samians reacted strongly (1908) and the entire Turkish fleet was sent to intimidate and suppress. So Sofoulis was forced to leave Samos. The Turkish authorities sentenced Sofoulis and his associates to death in absentia. In March 1912 Kopasis was assassinated. Five months later the Samians revolted and Sofoulis led fierce battles. The Turks withdrew and an armistice was signed on 23.9.1912.
The Samian National Assembly elected Sophoulis as its president. Shortly afterwards, the Sami National Assembly proclaimed the union with Greece. After the Balkan Wars, Sofoulis was appointed General Governor of Macedonia (1914). In 1915 he was elected as a member of the Samos Parliament and participated in the National Defence movement. He took over the Ministry of Interior. In the elections of 1923 he was elected as a member of the Parliament of Samos. He supported Alex. He supported Alexis Papanastasiou and advocated the abolition of royalty. He was elected deputy leader of the Liberal Party.
He served three times as Prime Minister for short periods and repeatedly as Speaker of the Parliament and MP. Later Minister of the Interior and Military Affairs. He gave a vote of confidence to I. Metaxas. He was arrested and imprisoned for 6 months by the Germans. Participated in various political formations with moderation and sought political compromise for national interest to avoid civil war. The state honoured him with the Grand Cross of the Order of the Saviour.