The cathedral's site on Plaza 10 de Noviembre carries layers of history older than the current building. The original church was begun in 1564 under the plans of master Juan Miguel de la Veramendi, who died before completing it. By 1568, official authorization for funding arrived from Lima. In 1572, Viceroy Francisco de Toledo restarted construction from the foundations, and the chronicler Bartolome Arzans de Orsua y Vela recorded that the church foundations and those of the great Mint House were laid on the same day in December of that year. The original temple had a single nave with a transept and Renaissance-style portals. Its lone tower stood for over a century before being expanded to two bodies in 1734 - an expansion that, combined with further ill-advised modifications, would eventually prove fatal.

Sanahuja was an unusual figure: a Franciscan friar who was also a trained architect, and the man who introduced Neoclassical style to Potosi. He designed not only the cathedral but also other religious and civil buildings in the city, working simultaneously across multiple commissions. His hand is most evident inside the cathedral, where the architectural spaces incorporate reredos - ornamental screens behind the altar - that Sanahuja himself designed. The integration of architecture and interior decoration was deliberate, giving the building a coherence that earlier Potosi churches, built piecemeal over decades, often lacked. Sanahuja moved to La Paz before the cathedral's completion and died there in 1834, two years before his masterwork was finished.

Inside the cathedral, the wealth of Potosi reveals itself. Important religious relics fashioned from gold and silver fill the interior - artifacts that survived the collapse of the old church or were commissioned for the new one. One sector of the building functions as a museum of religious art, displaying pieces that span the colonial and Republican periods. The organ was donated by Simon I. Patino, the Bolivian tin magnate who became one of the wealthiest people in the world during the early twentieth century. His gift linked the cathedral to a newer chapter in Bolivian mineral wealth: by the time Patino's fortune rose, silver had given way to tin as the country's dominant export, but the cathedral still stood as a monument to the older metal that built the city around it.

The cathedral was solemnly consecrated on April 4, 1838, during the presidency of Marshal Andres de Santa Cruz, who sponsored the ceremony. The timing was significant. Bolivia was barely thirteen years old, having been formed on August 6, 1825. The consecration of a grand cathedral under a Bolivian president, in a building begun under Spanish colonial authority, embodied the young nation's effort to claim continuity with the colonial past while asserting its independence from it. The cathedral faces Cerro Rico, the silver mountain that made Potosi one of the largest and richest cities in the world during the sixteenth and seventeenth centuries. Today the mountain looms behind the cathedral's stone facade as both backdrop and reminder - the source of the fortune that built everything on the plaza, and the reason anyone built a cathedral here at all.