[1] Moderate in his positions at the beginning of his political life, he advocated maintaining a degree of UGT cooperation with the dictatorial government of General Miguel Primo de Rivera, which permitted the union to continue functioning under his military dictatorship (which lasted from 1923 to 1930).

[2] This cooperation was the start of Largo Caballero's political conflict with Indalecio Prieto, who opposed all collaboration with Primo de Rivera.

Largo Caballero was Minister of Labor Relations between 1931 and 1933 in the first governments of the Second Spanish Republic, headed by Niceto Alcalá-Zamora, and in that of his successor Manuel Azaña.

In May he established mixed juries (jurados mixtos) to arbitrate in agrarian labour disputes, and introduced an eight-hour working day in the countryside.

[9] Largo dismissed fears of a military coup, and predicted that, were it to happen, a general strike would defeat it, opening the door to the workers' revolution.

While not immediately successful, further actions by rebellious army units sparked the Spanish Civil War (1936–1939), in which the republic was ultimately defeated and destroyed.

[14] On 4 November 1936 Largo Caballero persuaded the anarchist Confederación Nacional del Trabajo (CNT; "National Confederation of Labour") to join the government, with four members assigned to junior ministries including Justice, Health and Trade.

[17] Largo Cabellero's cabinet, formed on 4 September 1936 and reshuffled on 4 November 1936, consisted of:[18] Upon the defeat of the Republic in 1939, he fled to France.