Although the Nuevo Reino de Granada originally formed part of the Viceroyalty of Peru, it was the earliest settlement on the continent of South America. When Balboa, in 1514, reported his rich discoveries in Darien, no time was lost in sending out Pedro Arias Dávila as governor, who landed at Santa Marta. He took with him as bishop Fray Juan de Quevedo, who formed one of his council with a right to vote, thus founding at the start that curious complication of jurisdictions which exercised so unhappy an influence on the development of the Spanish colonies. The see of Santa Marta, however, was not founded until 1531 and, as settlements were pushed into the interior, Santa Fe de Bogotá was established as the capital, where the Audiencia, or high court, was organized in 1547 and governed the colony until 1564, when Andrés Díaz Venero de Leiva was sent out as president. It was not erected into a viceroyalty until 1719, from which it was reduced to its former state in a few years, to be restored again in 1740.

In 1532 the see of Cartagena was founded and, in 1547, that of Popayan. In 1553 came the Franciscan Fray Juan Barrios with a bull of Julius III by which the see of Santa Marta was transferred to Santa Fe and erected into an archbishopric, thus sundering it from the metropolis of Lima.