In 1857 PC candidate Mariano Ospina Rodríguez was elected president. The next year, his administration adopted a new constitution, which renamed the country the Grenadine Confederation, replaced the vice president with three designates elected by Congress, and set the presidential term at four years. With the draconiano faction disappearing as a political force, the golgotas took over the PL in opposition to the Conservative Ospina. General Mosquera, the former president and the governor of the department of Cauca, emerged as the most important Liberal figure. A strong advocate of federalism, Mosquera threatened the secession of Cauca in the face of the centralization undertaken by the Conservatives. Mosquera, the golgotas, and their supporters declared a civil war in 1860, resulting in an almost complete obstruction of government.

Because civil disorder prevented elections from being held as scheduled in 1861, Bartolomé Calvo, a Conservative in line for the presidency, assumed the office. In July 1861, Mosquera captured Bogotá, deposed Calvo, and took the title of provisional president of the United States of New Granada and supreme commander of war. A congress of plenipotentiaries chosen by the civil and military leaders of each department met in the capital in September 1861 in response to a call by the provisional government. Meanwhile, the war continued until Mosquera defeated the Conservatives and finally subdued the opposition in Antioquia in October 1862.

Shortly after taking power, Mosquera put the church under secular control and expropriated church lands. The property was not redistributed to the landless, however, but was sold to merchants and landholders in an effort to improve the national fiscal situation, which had been ruined by the war. As a result, the amount of land held under latifundios increased.