During the dictatorship of Miguel Primo de Rivera he conspired against the regime, and was imprisoned three times.

When the Second Republic was declared, he was named director of the Universidad Complutense de Madrid and advisor of State.

After the failure of Diego Martínez Barrio to form a government to restrain the military revolt of 17 July 1936, Azaña ordered Giral to form a new government constituted exclusively by republicans.

Then, with the fall of Talavera de la Reina and the Army of Morocco within reach of Madrid, Giral was forced to cede power to Francisco Largo Caballero.

In 1945 he succeeded Juan Negrín as prime minister of the Spanish Republican government in Exile until 1947.