The first bishop of the City of Antequera, Juan López de Zárate, occupied the San Juan de Dios temple as the cathedral from 1535.

However, in that same year, preparations began for the construction of the new cathedral, based on the basilical design used in Mexico City and Puebla.

The Cathedral of Our Lady of the Assumption went through several stages of construction until it reached its current form.

The first work began in 1535 and was completed in 1574. The design included three naves with quarry stone walls and pillars. The facade was austere, and the interior contained altars and retablos. Around 1667, the ecclesiastical authority started the construction of the vaults of the naves, the sacristy, and the chapter house, which were completed in 1678. In 1682, the side chapels were planned and finished in 1694.

In 1714, a strong earthquake caused serious damage, leading to the closure of the church. In 1724, the decision was made to rebuild it, and the project was entrusted to the architect Miguel de Sanabria. The project also included the creation of the vaults of the Sagrario Chapel and the Guadalupe Chapel. The reopening took place on April 21, 1733, by Bishop Fray Francisco Santiago y Calderón.

In 1890, the city council replaced the original top with a bell tower and clock, which was removed in the mid-20th century and replaced with the current top. In 1982, the atrium fence was removed and integrated into the Alameda de León, which connects to the city's main square.

The facade dates back to the 17th century and is made of green quarry stone in a baroque style. It has three doors with semi-circular arches. Several beautifully carved niches with figures of St. Peter, St. Paul, St. Joseph, St. Christopher, St. Marcial Obispo, St. Peter Martyr, St. Augustine, and St. Benedict, among others, can be seen.

The current towers were built in 1931 after the previous ones were knocked down by an earthquake.

Inside, there is an important collection of 18th-century paintings. The chapel of the Lord of the Lightning, wrapped in a legend that tells of a sunny day when a lightning bolt struck and caused a fire, is particularly notable. The only thing that survived was a Christ figure, which changed its color.