The 1866 rebellion led by Juan Prim and the revolt of the sergeants at San Gil 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 Council of Ministers with a liberal, but to overthrow Isabella herself, whom Spanish liberals and republicans began to see as the source of Spain's ineffectuality.

Her continual vacillation between liberal and conservative quarters had, by 1868, outraged moderados, progresistas, and members of the Unión Liberal and enabled, ironically, 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 Cádiz – the same place that Rafael del Riego had launched his coup against Isabella's father a half-century before. 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 Pavía 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.