Prior to the Spanish conquest the territory included in the modern department formed a part of the Kʼicheʼ Kingdom of Qʼumarkaj.

The kingdom was defeated by the Spanish under Pedro de Alvarado in a number of decisive battles fought near the city of Quetzaltenango, then known as Xelaju.

In the 19th century the territory of the modern department was included in the short-lived Central American state of Los Altos.

[5] The territory that came to be included within the modern department of Quetzaltenango was the scene of several decisive battles in February 1524 between Spanish conquistador Pedro de Alvarado and the Kʼicheʼ Kingdom of Qʼumarkaj.

Pedro de Alvarado had initially advanced with his army along the Pacific coast without opposition until they reached the Samalá River; this region formed a part of the Kʼicheʼ kingdom.

[6] Alvarado then turned to head upriver into the Sierra Madre mountains towards the Kʼicheʼ heartlands, crossing the pass into the fertile valley of Quetzaltenango.

The cavalry scattered the Kʼicheʼ and the army crossed to the city of Xelaju, modern Quetzaltenango, to find it deserted by its inhabitants.

[10] Pedro de Alvardo, in his 3rd letter to Hernán Cortés, describes the death of one of the four lords of Qʼumarkaj upon the approach to Quetzaltenango.

[13] This battle exhausted the Kʼicheʼ militarily and they asked for peace and offered tribute, inviting Pedro de Alvarado into their capital Qʼumarkaj.

[22] The government of Manuel Estrada Cabrera initially denied that the eruption had taken place in Guatemala, instead claiming that it had occurred in neighbouring Mexico.

[26] Average annual rainfall is 2,000 millimetres (79 in) in the municipality of Almolonga, and parts of the department at higher altitudes experience frost in the months from November through to March.

[38] The wide climatic variation within the department resulting from differences in altitude gives rise to a diverse range of agricultural products.

[39] These include apples, beetroot, cabbages, carrots, high quality coffee, common beans, maize, onions, peaches, plums, potatoes, radishes, turnips and wheat.

[39] Almolonga is the main producer of vegetables, both for the national market and for export, principally to Mexico and countries in Central America.

[39] Other products of the department include woolen textiles, cotton, silk, ceramics, alcoholic beverages and flour.

[38] Poorer high altitude areas of the department experience seasonal migration of workers to the Pacific lowlands in order to work on coffee, sugarcane and cotton plantations.

[59] Cerro Quiac is another small site on a hilltop in Cantel municipality,[60] dated to the Early Postclassic period (c. 950-1200 AD).

[112] Guatemalan historian Adrián Inés Chávez, who produced a Spanish translation of the Popul Vuh, was also from the department.