He agitated as a young man in the ranks of the radical republicans, as a follower of Ruiz Zorrilla. He practised a demagogic and aggressive journalistic style in the diverse publications that he directed (El País, El Progreso, El Intransigente and El Radical).
His populist and anticlerical speeches, as well as his intervention in diverse campaigns against the governments of the Restoration, made him very popular among workers in Barcelona, who later constituted the base of a loyal electorate. He was chosen as a deputy for the first time in 1901, and again in 1903 and 1905, as a member of the Republican Union party that he had helped to form with Nicolás Salmerón. The defection of Salmerón to the Catalan Solidarity coalition in 1906 led Lerroux to form the Radical Republican Party (1908) and headed the struggle against increasing Catalan nationalism. He had to go into exile on several occasions, first to escape condemnation dictated by one of his articles (1907) and later fleeing from governmental repression in response to the Tragic Week in Barcelona (1909).
After returning to Spain, he agreed to join the Socialist-Republican Conjunction, and he was elected as a deputy again in 1910. Afterwards he was involved in a series of scandals that moved him away from his Barcelona electorate, between corruption accusations (until the point of which there was a change of district, appearing for Córdoba in 1914). Under the dictatorship of Miguel Primo de Rivera (1923-30), his party was debilitated by the split with the Radical-Socialists lead by Marcelino Domingo (1929). However, he continued to be active in politics, participating in the revolutionary committee that prepared the overthrow of King Alfonso XIII and the proclamation of the Second Spanish Republic in 1931.
Under the republican regime he regained a leading political role. He was part of the coalition of leftists that supported the reforms of Manuel Azaña's government during the first biennium (1931-33), during which time he served as minister of State (1931). He was elected Prime Minister of the Republic on 19 November 1933, mainly because the President did not wish to name José María Gil-Robles y Quiñones, leader of the CEDA, prime minister. He sided with the right-wing opposition and became, from 1933-36, part of the conservative majority that came to power. He was named prime minister three times between 1933 and 1935 and he occupied the distinguished ministerial portfolios of War (1934) and State (1935). After distinguishing himself in the repression of the attempted workers revolution of 1934, he was discredited again before public opinion by the Straperlo affaire (a case of corruption bound to casino authorization), that completely broke his alliance with the right and even weakened his position within the party. In the elections of 1936 he was not even elected as a deputy, and when that same year the Spanish Civil War (1936-39) exploded, he preferred to place himself out of danger in Portugal. He returned to Spain in 1947.