Founded in 1541 by Jorge Robledo as Villa de Santafé on the western bank of the Cauca River, in 1545 it received the coat of arms and the title of City of Antioquia from King Philip II of Spain.

The municipal area is 493 square kilometres (190 sq mi), with a mountainous territory within the Central Cordillera of the Andes and watered by both the Cauca and the Tonusco Rivers.

The climate of Santa Fe de Antioquia is tropical and humid, typical of Colombia's Cauca River valley, due to its low altitude and its geographical location near the equator.

This pleasant weather has allowed tourism to develop in the city, which has been filled with hostels, hotels and water parks frequented by people from Medellín and the near metropolitan area.

The opening of the Tunnel of the West (which reduces the time and the distance between the locality and Medellín) in 2006 has allowed hundreds of tourists to arrive each weekend, stimulating the vocation of the vicinity as a summer vacation site.