He served numerous times as a cabinet minister, starting in 1923, in a political career that spanned more than five decades.

As a young man, he became involved in politics as a supporter of the Liberal leader Eleftherios Venizelos, who made him governor of Chios after the Balkan Wars.

During the political crisis surrounding Greece's entry into the First World War, Papandreou was one of Venizelos's closest supporters against the pro-German monarch, King Konstantínos I.

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.

The liberal political forces in the Kingdom of Greece were gravely weakened by internal disputes and suffered electoral defeat from the conservatives.

Papandreou continuously accused Sofoklis Venizelos for these maladies, considering his leadership dour and uninspiring.

After the elections of "violence and fraud" of 1961, Papandreou declared a "Relentless Struggle" against the right-wing ERE and the "parakrátos" (deep state) of the right.

Andreas disagreed with his father on many important issues, and developed a network of political organizations, the "Democratic Leagues" (Dimokratikoi Syndesmoi) to lobby for more progressive policies.

Finally, the King engineered a split in the Centre Union, and in July 1965, in a crisis known as the Apostasia or Iouliana, he dismissed the government following a dispute over control of the Ministry of Defence.

After the April 1967 military coup by the Colonels' junta led by George Papadopoulos, Papandreou was arrested.

During the junta and after his death he was often referred to affectionately as "ο Γέρος της Δημοκρατίας" (o Géros tis Dimokratías, the old man of Democracy).