After the Village of Antequera was founded, the need arose to have a place where authorities of this new settlement could attend town affairs. It was then, the Town Council built its first Government Building in 1576, on the same site of the current Government Palace. It is a known fact that, during the 17th century, and first quarter of the 18th century, the construction was improved considerably. The original adobe were replaced with quarry-stone, and the straw roof was changed in favour of more solid covering. In 1775, the Town Council hired the services of Architect Nicolas de Lafora, to design and build a new construction, which he finished in 1783. Unfortunately, the earthquakes of 1787 and 1801 did considerable damage to the building, forcing the site to be abandoned for a long time. The current palace was built in 1832, and after several delays, was formally inaugurated on September 15, 1884. The earthquake of 1931 did considerable damage, but the Palace was rebuilt between 1936 and 1948.

In 1980, the artist, Arturo Garcia Bustos, decorated the interior walls of the Palace’s main staircase, which leads to the upper level. This mural shows three different eras. The left mural expresses Pre-Hispanic traditions, reflecting lifestyles of Zapotecos, Mixtecos and Mexicas. On the right, are passages from the times of the conquest. The centre mural depicts the time of the Independence. The last has a picture of José Maria Morelos y Pavon, printing the first Oaxacan journal, "El Correo del Sur" [Southern Courier]. Other important Mexican heroes also appear here, such as: Benito Juárez, Margarita Maza, José Maria Morelos and Ricardo Flores Magon.

Garcia Bustos painted a second mural in 1987 on the ceiling and walls of the side staircase, which leads to the east patio of the Government Palace. This mural painting represents the birth of the Universe, from the mystical point of view of Pre-Hispanic Oaxacan cultures. Pre-Hispanic cosmogony of life and death, as well as some more mundane aspects of life during those times is shown on the vault.

The central mural portrays water, fertility of the soil and education. The mural on the right depicts the tree of life, a woman, naked from the waist up with her waist loom, a sorcerer or high priest, the huge Monte Albán Plaza, and a scribe painting some codex. The left mural shows daily life in the Isthmus, a day at a marketplace, as well as some Huave fishermen from San Mateo del Mar, with their nets and musical instruments. There is also a portrait of the Huautla de Jimenez area, represented by the goddess of the soil and two priestesses dressed in traditional Mazatec attire, known as a Huipil.