In 1909 he achieved a position at the Main Directorate of the Registries and practiced the profession of civil law notary, and traveled to Paris in 1911. He became involved in politics and in 1914 he joined the Reformist Republican Party led by Melquíades Álvarez. He collaborated on newspapers like El Imparcial and El Sol. He directed the magazines Pluma and España between 1920 and 1924, founding the former with his brother-in-law Cipriano Rivas Cherif. He was secretary of the Ateneo de Madrid (1913-1920), becoming its president in 1930. He was a candidate for the province of Toledo in 1918 and 1923, but lost on both occasions. In 1926 he founded Acción Republicana with José Giral.

A strong critic of the dictatorship of Miguel Primo de Rivera, he published an energetic manifesto against the dictator and King Alfonso XIII in 1924. He later participated in the Pact of San Sebastián in 1930, which would form the nucleus of the future republican government that arose after favorable results to the republican candidacies in the municipal elections of April 12, 1931, and the subsequent abandonment of the country by King Alfonso.

He was named Minister of War in the provisional Government of the Second Republic on April 14, and replaced Don Niceto Alcalá-Zamora as provisional prime minister (in October of the same year), due to Alcalá-Zamora's resignation over the subject of the religious question. As prime minister of the Republican coalition government with the Spanish Socialist Workers' Party (PSOE), he carried out the main reforms anticipated in the republican program: the reformation of the Spanish Army - to determine its size in agreement with the capacity of the country, the agrarian reform, and the education reform - suppressing religious activities and promoting public ones.

Those issues, along with the existing social agitation in a large extent of the country would carry him into conflict with various factions, especially with the Roman Catholic Church and parts of the army, finally leading to the events of Casa Viejas, Castilblanco y Arnedo, which forced his resignation on September 8, 1933. The triumph of the coalition formed by Alejandro Lerroux's Radical Republican Party and the Confederación Española de Derechas Autónomas (CEDA) of José María Gil-Robles y Quiñones on November 19, 1933, caused him to temporarily withdraw from politics and return to literary activity.

The political distance lasted only a short while, and in 1934 he founded the Republican Left party, the fruit of the fusion of Acción Republicana with the Radical Socialist Republican Party, led by Marcelino Domingo, and the Organización Republicana Gallega Autónoma (ORGA) of Santiago Casares Quiroga. In 1934 serious revolutionary events took place in Asturias and Barcelona. Accused of instigating the riots, he was jailed on board the destroyer Sanchez Barcáiztegui anchored in the port in Barcelona, but was later acquitted.

After his release in January 1935, he initiated a political campaign that gave rise to the creation of the Popular Front, a major left-wing coalition that won the elections of February 16, 1936.

On May 10 of that year, he was elected President of the Republic after the removal of Alcalá-Zamora, a position that he occupied during the Spanish Civil War (1936-1939). His futile attempts to warn the different republican political forces about the dangers from its lack of unity left him isolated in the government.

Azaña's memoirs would faithfully reflect conflicts with governing Republican leaders like PSOE's Francisco Largo Caballero and Juan Negrín. With the fall of Barcelona on January 26 and Gerona on February 5 1939 to Francisco Franco's Nationalist troops, he fled to France (the same day as Gerona's fall), and later submitted his resignation as President of the Republic.

He lived in exile in France, being trapped there by the Nazi German occupation regime. The Vichy French authorities refused to allow his coffin to be covered with the Republican flag.