Starting in 1536, the conquistador Gonzalo Jiménez de Quesada explored the extensive highlands of the interior of the region by following the Magdalena River into the Andean cordillera.

Charles V ordered the establishment of an audiencia, a type of superior court that combined executive and judicial authority, at Santafé de Bogotá in 1549.

[5] In Santa Fé de Bogotá of the New Kingdom of Granada shall reside another Royal Audiencia and Chancery of ours, with a president, governor and captain general; five judges of civil cases [oidores], who shall also be judges of criminal cases [alcaldes del crimen]; a crown attorney [fiscal]; a bailiff [alguacil mayor]; a lieutenant of the Gran Chancellor; and the other necessary ministers and officials, and which will have for district the provinces of the New Kingdom and those of Santa Marta, Río de San Juan, and of Popayán, except those places of the latter which are marked for the Royal Audiencia of Quito; and of Guayana, or El Dorado, it shall have that which is not of the Audienicia of Hispaniola, and all of the Province of Cartagena; sharing borders: on the south with said Audiencia of Quito and the undiscovered lands, on the west and north with the North Sea and the provinces which belong to the Royal Audiencia of Hispaniola, on the west with the one of Tierra Firme.

Because of the slowness in communications between Lima and Bogotá, the Bourbons decided to establish an independent Viceroyalty of New Granada in 1717 (which was reestablished in 1739 after a short interruption).

The governor-president of Bogotá became the viceroy of the new entity, with military and executive oversight over the neighboring Presidency of Quito and the provinces of Venezuela.