From 1903 to 1905 Orlando served as minister of education under King Victor Emanuel III.  He became minister of justice in 1907 a position he held until 1909.  He was re-appointed to the justice post in 1914 until he was nominated minister of the interior in 1916 in which capacity he served until 1917.

Orlando was a strong proponent of Italy's participation in World War I on the side of the Allies who had secretly promised Orlando significant territorial concessions to Italy in case of Italy's participation in the conflict.

in 1917 Orlando was elected Prime Minister.  In that function, he headed the Italian delegation to the Paris Peace Conference in 1919.  However, he was unable to obtain the territorial concessions for Italy  which drastically weakened his position which he lost mid of 1919.

In December of 1919 he was elected president of the chamber of deputies.  Initially he supported Benito Mussolini's fascist government that had been established in 1922.  However, when the fascists killed Giacomo Matteotti -a prominent socialist leader- in 1924, Orlando no longer supported Mussolini's government and 3 years later he resigned from the chamber of deputies and served thereafter in the constituent assembly.