Pro-Greek agitation and the reaction of the pro-autonomy faction led to increased tensions, and in May 1908 the Prince, Andreas Kopasis Omoudopoulos, asked for the intervention of the Turkish military.

During the dramatic events, which led to the resignation of Panagis Tsaldaris and the restoration of the constitutional monarchy, Themistoklis Sofoulis kept a moderate stance, which was appreciated by King George II.

During Ioannis Metaxas' dictatorship, Sofoulis remained aloof from developments, although the regime's increasing tendency towards Fascism caused him to send a warning letter to King George II in April 1939.

During the Axis Occupation of Greece, Sofoulis, like most of the established politicians, remained rather passive, although he maintained contacts to the Allies in the Middle East.

Themistoklis Sofoulis served as head of the Greek government from 1945 to 4 April 1946, but in the legislative elections of 1946 he suffered defeat at the hands of the People's Party of Konstantinos Tsaldaris.

His efforts to prevent the outbreak of the Greek Civil War by reaching out to the Communists and offering amnesty were rebuffed by the People's Party, leading Sofoulis to abstain from the government of Dimitrios Maximos.

Sofoulis undertook further efforts to end the conflict, negotiating with KKE for a general amnesty and a possible coalition government between it and the Liberals, provided that EAM's new armed force, known as the "Democratic Army of Greece", disarmed.

This ability of his allowed him to lead the country during the Civil War and to convince General Alexandros Papagos to return to active service, although the latter belonged to the right wing of the political spectrum.