Francis was born at Aranjuez, Spain, the second son (first to survive infancy) of Infante Francisco de Paula of Spain, and of his wife (and niece), Princess Luisa Carlotta of Naples and Sicily. He was named after Saint Francis of Assisi. Francis' paternal grandparents were Charles IV of Spain and Maria Luisa of Parma. Their daughter, María Isabella of Spain, and Francis I of the Two Sicilies were his maternal grandparents.

Francis married Isabella, his double first cousin, on 10 October 1846. There is evidence that Isabella would rather have married his younger brother, Infante Enrique, Duke of Seville, and complained bitterly about her husband's effeminate habits after their first night together. Twelve children were born during the marriage, of whom five reached adulthood: Isabella, Princess of Asturias (1851–1931): married her mother's and father's first cousin Prince Gaetan, Count of Girgenti. Alfonso XII of Spain (1857–1885). Maria de Pilar (1861–1879). Infanta María de la Paz (1862–1946): married her paternal first cousin Prince Louis Ferdinand of Bavaria. Infanta Eulalia (1864–1958): married her maternal first cousin Don Antonio de Orléans y Borbón, Infante of Spain, Duke of Galliera. There has been considerable speculation that some or all of Isabella's children were not fathered by Francis; this has been bolstered by rumours that Francis was either homosexual or physically unable to complete the sex act.

Starting in 1864, Francis acted as president of the Spanish Privy Council (Consejo del Reino). In 1868 he went into exile with his wife in France and adopted the incognito title of Count of Moratalla. In 1870 Francis and Isabella were amicably separated and, with time, became good friends, which they had certainly not been while she was Queen regnant. The 1874 restoration placed his son Alfonso XII on the throne. In 1881 Francis took up residence at the château of Épinay-sur-Seine (currently the city hall). He died there in 1902. His wife Isabella and two of his daughters, Isabella and Eulalia, were present at his deathbed.

13 May 1822 – 10 October 1846: His Royal Highness The Duke of Cádiz 10 October 1846 – 25 June 1870: His Majesty The King of Spain 25 June 1870 – 17 April 1902: His Majesty King Francis of Spain

Knight of the Order of the Golden Fleece Knight of the Royal and Distinguished Spanish Order of Charles III Collar of the Order of Isabella the Catholic Foreign : Knight of the Order of the Most Holy Annunciation : Knight Grand Cross of the Order of Saint-Charles : Knight of the Royal Order of the Seraphim