Lerroux agitated as a young man in the ranks of the radical republicans, as a follower of Manuel 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 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, Lerroux agreed to join the Republican–Socialist 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, with corruption accusations forcing him into a change of district, appearing for Córdoba in 1914).
Under the dictatorship of Miguel Primo de Rivera (1923–30), his party was debilitated when its left wing, led by Marcelino Domingo, left to form the Radical Socialist Republican Party in 1929. However, he continued to be active in politics, attending the revolutionary committee that produced the Pact of San Sebastián with the intention of overthrowing King Alfonso XIII and proclaiming a republic.
Under the republican regime, Lerroux regained a leading political role, being appointed prime minister three times between and occupying the distinguished ministerial portfolios.
He was part of the coalition of leftists that supported the reforms of Manuel Azaña's government during the first biennium (1931–1933), during which time he served as minister of State (1931) and as Minister of Foreign Affairs between 14 April 1931 and 16 December 1931. From 12 September to 9 October 1933, he was Prime Minister.
After the victory of the Spanish Confederation of the Autonomous Right (CEDA) in the elections of autumn 1933, Lerroux again became prime minister, mainly because the President did not wish to appoint CEDA leader José María Gil-Robles y Quiñones. As such, he served from 16 December 1933 to 28 April 1934 and again from 4 October 1934 to 25 September 1935. He also served as minister of war (1934), state (1935) and foreign affairs (1935).
After distinguishing himself in the repression of the attempted workers revolution of 1934, he was discredited by the Straperlo affaire (a case of corruption bound to gambling legalization) that completely broke his alliance with the right and even weakened his position within the party.
In the elections of 1936, Lerroux was not even elected as a deputy, and when that same year the Spanish Civil War broke out, he preferred to place himself out of danger in Portugal. He returned to Spain in 1947.