At the time of Spanish contact, Chiquimula was part of the indigenous kingdom of Chiquimulha, or Payaqui, governed from its capital at Copanti (now Copan, in Honduras).

[6] The first Spanish reconnaissance of this region took place in 1524 by an expedition that included Hernando de Chávez, Juan Durán, Bartolomé Becerra and Cristóbal Salvatierra, amongst others.

The indigenous population soon rebelled against excessive Spanish demands, but the rebellion was quickly put down in April 1530.

[8] However, the region was not considered fully conquered until a campaign by Jorge de Bocanegra in 1531–1532 that also took in parts of Jalapa.

[12] The department has numerous mineral deposits, and silver has been mined there since the Spanish colonial period.

Climate change has notably affected the department, with maximum temperatures reaching 42 °C (108 °F), and a decrease in rainfall contributing to scarcity of foodstuffs.

[16] Poverty levels tend to be higher in the northern portions of the department, and lower in the south.

[21] In 2013, 25.5% of the population were recorded as illiterate, demonstrating a year-on-year reduction in illiteracy rates over the previous five years.

[30] In January 2021, a caravan of between 7,000- 9,000 migrants from Honduras, who had departed from San Pedro Sula was heading towards the United States and broke through police lines at Vado Hondo, a village near the city of Chiquimula.