O'Donnell was a strong endorser of the liberal Cristinos and the regency of Maria Cristina during the 1830s. When General Baldomero Espartero seized power during 1840, O'Donnell went into exile with Maria Cristina, and was involved in an attempted coup against Espartero during 1841. O'Donnell was soon back in power and was sent to Cuba as Captain General during October 1843. He is credited with the massacre of 1844 known as the repression of La Escalera. Thousands of slaves and free-coloured people in Cuba were confined in dungeons, were tortured and executed in what became known as the 'year of the lash'. During 1854, he made a pronunciamiento against the government and was named Prime Minister for a time. He served as War Minister of the Espartero government. The Crimean War caused an increase of grain prices due to the blockade of Russia, causing a famine in Galicia during 1854. Riots against power looms spread through Spain, and General O'Donnell intervened, marching on Madrid. Espartero resigned power in O'Donnell's favour on 14–15 July 1856, and Isabella II asked him to form a government as the 44th Prime Minister of Spain. For his new administration, O'Donnell formed the Unión Liberal Party, which was designed to combine Progressive, Moderate, and Carlist factions. O'Donnell attempted to define moderate policies for Spain with this new party, advocating laissez-faire policies and confiscating church land. He was soon dismissed after only a few months in power on 12 October, and two years of reaction followed. In later governments, he was more careful. O'Donnell's two later administrations worked laboriously to attract foreign investment to improve Spain's railroad infrastructure. He failed to achieve much economic growth, however, and increased industry only in Basque country and Catalonia, both of which already had substantial industrial centres. He was a proponent of a new and aggressive imperial policy, intended principally to expand Spanish territory in Africa, particularly after French successes in Algeria. In the first administration he was twice at the same time the 136th Minister of Foreign Affairs and the 48th Prime Minister of Spain between 30 June 1858 and 2 July 1858, and again as the 138th Minister of Foreign Affairs between 21 October 1860 and 18 January 1863, remaining again solely as Prime Minister until 26 February 1863. His second term as the 53rd Prime Minister started on 21 October 1860. He took a brief respite from his government during 1860 to command the Spanish army at the battle of Tetuan during its Spanish-Moroccan War, overseeing the capture of Tétouan. He was rewarded for his abilities in the campaign with the title Duke of Tetuán. During 1866 he repressed a revolt commanded by General Juan Prim, and was subsequently dismissed by the Queen for the brutality of his regime on 11 July 1866. He was the 103rd Grand Cross of the Order of the Tower and Sword.
Family
He was succeeded in his titles by his nephew, son of his brother Carlos O' Donnell y Jorris and wife María del Mar Alvarez de Abreu y Rodríguez de Albuerne, Carlos O' Donnell y Alvarez de Abreu, 2nd Duke of Tetuán, 2nd Count of Lucena and also 9th Marquess of Altamira, married in Madrid on 1 June 1861 to María Josefa de Vargas y Díez de Bulnes.