The town was elevated to an honorary Mexican status in June 1843 in remembrance of The siege of Huajuapan, a battle between the royal army and the insurgents led by José María Morelos.

[2] The first inhabitants of this area are called the Ñuu Yate (ancient people) who formed their settlement in what is now the town of Huajuapan around 400 BCE.

Prior to this the low parts of the valley were not organized and merchants travelling through the area often suffered from highway bandits.

[2] During the Mexican War of Independence, this village was subject to a siege by insurgent forces that lasted 111 days.

Resistance of the town was finally broken in June 1812 by Coronel Valerio Trujano, with help from General José María Morelos.

[9] The hill now known as the Cerro de las Minas, which dominates the valley of Huajuapan, was the site of an ancient Mixtec community.

In this grave, large quantities of ceramics were found of native design as well as a multicolored urn with an image of the god of wind or fire, with a brazier on its head.

One is called Ñudee, which is the original Mixtec name for Huajuapan and means "place of the brave," and covers the era between 400 BCE and 250 CE.

The area began to decline after 800 CE, possibly due to military pressure from lords in other regions.

The Mixteca region of which Huajuapan is part has a high rate of immigration to the United States and remittances are important for the local economy.

[2] The festival of the Señor de los Corazones is related to the siege that Huajuapan endured for 111 days during the War of Independence.

Processions, organized by a brotherhood created especially for this purpose, are held for each day of the novena, with participants carrying an image of the Señor de los Corazones.

On the 24th one last major procession for the image wanders through the main streets of the city from eight in the morning to three in the afternoon, from the Chapel of the Sagrario to the cathedral.

[2] An important regional university (Universidad Tecnológica de la Mixteca) has been operating in Huajuapan since 1991 with the aim of promoting development of the area.