Because of an article calling on King Konstantínos to abdicate, he was imprisoned by the royalist regime and later he narrowly escaped assassination from royalist extremists in Lesbos. From January to October 1923, he served as interior minister in the cabinet of Stylianos Gonatas. In the December 1923 elections, he was elected as a Venizelist Liberal Party member of parliament for Lésvos, and served as finance minister for just 11 days in June 1925, education minister in 1930–1932 and transport minister in 1933. As minister of education he reformed the Greek school system and built many schools for the children of refugees of the Greco-Turkish War. During the dictatorship of Pangalos, he was again imprisoned. In 1935, he set up the Democratic Socialist Party of Greece. The same year, a royalist coup by General Geórgios Kondylis took place for the re-establishment of monarchy and he was placed in internal exile. A lifelong opponent of the Greek monarchy, he was again exiled in 1938 by the Greek royalist dictator Ioannis Metaxas. Following the Axis occupation of Greece in the Second World War, he was imprisoned by the Italian authorities. He later fled to the Middle East and joined the predominantly Venizelist government-in-exile based in the Kingdom of Egypt. With British support, King Geórgios II appointed him as Prime Minister, and under his premiership took place the Lebanon conference (May 1944) and later the Caserta Agreement (September 1944), in an attempt to stop the crisis in Greece and the conflicts between EAM and non-EAM forces (a prelude of the civil war) and establish a national unity government. After the evacuation of Greece by the Axis powers, he entered Athens (October 1944) as Prime Minister of the Greek government-in-exile with some units of the Greek Army and the allied British. During the same month, he became Prime Minister in the , which had succeeded the Greek government-in-exile. He tried to normalise the highly polarised situation between the EAM and non-EAM forces, collaborating mainly with Lieutenant-General Sir Ronald Scobie, who was, after the Caserta agreement, responsible for all the Allied forces. Although he resigned in 1945, after the "Dekemvriana" events, he continued to hold high office. From 1946–1952 he served as labour minister, supplies minister, education minister, finance minister and public order minister.