The site currently occupied by the Castle of Santa Cecilia was first established as a mining operation in the Hacienda de San Francisco Javier. Following centuries of major silver production and refining on-site, the hacienda's operations slowly declined, along with those of the entire city of Guanajuato. By 1916, it no longer functioned as a mine.

The hacienda's buildings were turned into a hospice and hospital for the first decades of the 20th century. Eventually, the buildings were demolished and the grounds were purchased by Don Manuel Quezada Brandy, who planned to develop a hotel.

A mine shaft known as Santa Cecilia was one of the last mining-related facilities to remain on-site, and it eventually inspired the name of the hotel. Construction on the building, inspired by medieval European castle architecture, began in 1951 and was completed a year later. The hotel originally had 20 rooms in total. Following renovations and expansions, it currently has 110 rooms.

Its installations have been used as a set for several Mexican films and series, and the hotel has hosted celebrities including Mexican Golden Age film stars Cantinflas and María Félix, as well as classic rockstar Alex Lora.

Castle purists will be glad to know that some of the most notable international personalities hosted by the hotel include actual European royalty, as Queen Elizabeth II of the United Kingdom and King Juan Carlos I of Spain have stayed here. Given that it was not built for defensive purposes however, Santa Cecilia is not a fully official castle, although it still makes for a palatial sight in the hills of Guanajuato.