An 1866 rebellion led by General Juan Prim and a revolt of the sergeants at San Gil barracks (Madrid) sent a signal to Spanish liberals and republicans that there was serious unrest with the state of affairs in Spain that could be harnessed if it were properly led.

Liberals and republican exiles abroad made agreements at Ostend in 1866 and Brussels in 1867. These agreements laid the framework for a major uprising, this time not merely to replace the president of the government with a liberal, but to overthrow Isabella herself, whom Spanish liberals and republicans began to see as the source of Spain's inefficacy.Her continual vacillation between liberal and conservative quarters had, by 1868, outraged moderados, progresistas, and members of the Unión Liberal and enabled a front that crossed party lines. Leopoldo O'Donnell's death in 1867 caused the Unión Liberal to unravel; many of its supporters, who had crossed party lines to create the party initially, joined the growing movement to overthrow Isabella in favor of a more effective regime.The die was cast in September 1868, when naval forces under admiral Juan Bautista Topete mutinied in Cadiz – the same place that Rafael del Riego had launched his coup against Isabella's father a half-century before.

Narváez deserted the queen, as did her chief minister, Luis González Bravo. Generals Juan Prim and Francisco Serrano denounced the government and much of the army defected to the revolutionary generals on their arrival in Spain. The queen made a brief show of force at the Battle of Alcolea, where her loyal moderado generals under Manuel Pavia were defeated by General Serrano. Isabella, then, crossed into France and retired from Spanish politics to Paris, where she would remain until her death in 1904. Juan Prim, Spanish general.

Prim was an architect of the 1868 revolution against Queen Isabella IIThe revolutionary spirit that had just overthrown the Spanish government lacked direction; the coalition of liberals, moderates, and republicans were now faced with the incredible task of finding a government that would suit them better than Isabella. Control of the government passed to Francisco Serrano, an architect of the revolution against Baldomero Espartero's dictatorship. The Cortes initially rejected the notion of a republic; Serrano was named regent while a search was launched for a suitable monarch to lead the country. A truly liberal constitution was written and successfully promulgated by the cortes in 1869 – the first such constitution in Spain since 1812.The search for a suitable king proved to be quite problematic for the Cortes.

The republicans were, on the whole, willing to accept a monarch if he was capable and abided by a constitution. Juan Prim, a perennial rebel against the Isabelline governments, was named regent in 1869 and remarked that "to find a democratic king in Europe is as hard as to find an atheist in Heaven!" (Pierson 25)The aged Espartero was brought up as an option, still having considerable sway among the progresistas; even after he rejected the notion of being named king, he still gained eight votes for his coronation in the final tally. (Esdaile 302) Many proposed Isabella's young son Alfonso (the future Alfonso XII of Spain), but many thought that he would invariably be dominated by his mother and would inherit her flaws. Ferdinand of Saxe-Coburg, the former regent of neighboring Portugal, was sometimes raised as a possibility. A nomination offered to Prince Leopold of Hohenzollern-Sigmaringen would trigger the Franco-Prussian War.

In August 1870, an Italian prince, Amadeo of Savoy, was selected. The younger son of Victor Emmanuel II of Italy, Amadeo had less of the troublesome political baggage that a German or French claimant would bring, and his liberal credentials were strong. He was duly elected King as Amadeo I of Spain on November 3, 1870. He landed in Cartagena on November 27, the same day that Juan Prim was assassinated while leaving the Cortes.

Amadeo swore upon the general's corpse that he would uphold Spain's constitution. He only lasted two years, leading to the establishment of the first Spanish Republic. That in turn also lasted two years, but no political force was willing to restore Isabella; instead Isabella's son was proclaimed King Alfonso XII in 1875.