In its origins this city was a diverse ethnic settlement that brought together Tlaxcaltecas, Otomis, Purépechas, Guachichiles and Spaniards, and it is a significant example of cultural blending in this region of the country. It was founded in 1583, at the site where Friar Diego de la Magdalena had gathered groups of Guachichil indigenous peoples who had first arrived in the region in the 13th century.

San Luis Potosí owes its name to Louis IX, king of France. On 3 November 1592 it was founded as the Pueblo de San Luis Mesquitique; subsequently, on 30 May 1656, the Viceroy Francisco Fernández de la Cueva, Duke of Alburquerque, granted the Pueblo y Minas del Potosí the right to be established as a city. The name Mesquitique was changed to Potosí in reference to the wealth of the mines in the San Pedro mountains, comparable to the Potosí mines in Bolivia.

The first villages were settled over the 16th century, previously separate and now forming the city’s neighborhoods: Tlaxcalilla, Santiago and San Miguelito; to which were added San Sebastián, Tequisquiapan, Montecillo, San Juan de Guadalupe and Tenería in the 16th century, La Soledad in the 18th century and Saucito in the 19th century.

San Luis Potosí became the largest Intendencia of all New Spain, and by 1787 it encompassed the jurisdiction of the present-day states of San Luis Potosí, Tamaulipas, Nuevo León, Coahuila and Texas. It underwent extensive social, political and above all economic development to become the third-most important city in all the viceroyalty, behind only Mexico and Puebla.

In the 19th century, the city was a primordial player in the republican cause, leading President Benito Juárez to declare it the capital of the country in 1863 and again in 1867. On this second occasion, it was in the city hall that the death sentence of Ferdinand Maximilian von Habsburg was signed.

Thanks to its historical, political and cultural value, the city of San Luis Potosí was declared a Zone of Historical Monuments on 19 December 1990; the conservation perimeters A and B bound an area of 1.93 km2 comprising 218 city blocks with building constructed between the 16th and 19th centuries. Of these, 18 were intended for religious worship, including most notably the Cathedral of Nuestra Señora de la Concepción, the Antiguo Seminario Conciliar, the former monasteries and churches of San Francisco and San Agustín; the churches of Nuestra Señora del Rosario, San Juan de Dios, the Sagrario or the Compañía, Loreto, San Miguel Arcángel, El Carmen, San José, Espíritu Santo, Nuestra Señora de la Salud, San Sebastián and its annexes, and that of the Tercera Orden, together with the chapels of Aránzazu and Guadalupe.

Other historical buildings were intended for the purposes of public education, welfare, service and embellishment, or use by the civil and military authorities, including: the seat of government and city hall, the Royal Treasury, the La Paz Theater, the central university building, the monumental palace and the water tower.

In the year 2010, San Luis Potosí was enrolled as a UNESCO World Heritage Site.