The first construction is attributed to Juan Díaz and Friar Bartolomé de Olmedo, clergymen who came with Hernán Cortés' forces. Initially, it was a chapel made of adobe with a thatched roof dedicated to Santa Catalina.

When the Villa of Antequera was declared a diocesan seat, the chapel was rebuilt with brick and tile to fulfill this new function. For this reason, this temple has been considered the first cathedral of Oaxaca. After the new cathedral was completed, the chapel fell into disuse and was finally destroyed by an earthquake in 1662.

The new construction was made in 1699 when the Juaninos monks arrived. Later, they erected the convent and hospital, which, when completed in 1703, began to be called San Juan de Dios. Over time, the grounds occupied by the hospital and convent were taken over by what is now the 20 de Noviembre market.

In 1864, the temple was destroyed by a fire, and three years later, it was reconstructed and consecrated in 1890.

The San Juan de Dios Temple was the first church in Oaxaca where the first mass was held at the foot of a huaje tree because the Atoyac River used to pass there, which was later diverted to the foothills of Monte Albán.

The temple has a single nave with a choir. Inside, there are some 17th-century oil paintings depicting episodes from Oaxaca's history, such as the first mass, the baptism of the Zapotec king Cosijoeza, the La Cruz de Huatulco, and the revolt in which the Cajonos martyrs were sacrificed. These martyrs were beatified in 2002 by Pope John Paul II. The chapel dedicated to the Lord of Mercy stands out.