In a protracted conflict during the Spanish colonization of the Americas, Spanish colonisers gradually incorporated the territory that became the modern country of Guatemala into the colonial Viceroyalty of New Spain. Before the conquest, this territory contained a number of competing Mesoamerican kingdoms, the majority of which were Maya. Many conquistadors viewed the Maya as "infidels" who needed to be forcefully converted and pacified, disregarding the achievements of their civilization. The first contact between the Maya and European explorers came in the early 16th century when a Spanish ship sailing from Panama to Santo Domingo was wrecked on the east coast of the Yucatn Peninsula in 1511. Several Spanish expeditions followed in 1517 and 1519, making landfall on various parts of the Yucatn coast. The Spanish conquest of the Maya was a prolonged affair; the Maya kingdoms resisted integration into the Spanish Empire with such tenacity that their defeat took almost two centuries.Pedro de Alvarado arrived in Guatemala from the newly conquered Mexico in early 1524, commanding a mixed force of Spanish conquistadors and native allies, mostly from Tlaxcala and Cholula. Geographic features across Guatemala now bear Nahuatl placenames owing to the influence of these Mexican allies, who translated for the Spanish. The Kaqchikel Maya initially allied themselves with the Spanish, but soon rebelled against excessive demands for tribute and did not finally surrender until 1530. In the meantime the other major highland Maya kingdoms had each been defeated in turn by the Spanish and allied warriors from Mexico and already subjugated Maya kingdoms in Guatemala. The Itza Maya and other lowland groups in the Petn Basin were first contacted by Hernn Corts in 1525, but remained independent and hostile to the encroaching Spanish until 1697, when a concerted Spanish assault led by Martn de Ursa y Arizmendi finally defeated the last independent Maya kingdom.

Spanish and native tactics and technology differed greatly. The Spanish viewed the taking of prisoners as a hindrance to outright victory, whereas the Maya prioritised the capture of live prisoners and of booty. The indigenous peoples of Guatemala lacked key elements of Old World technology such as a functional wheel, horses, iron, steel, and gunpowder; they were also extremely susceptible to Old World diseases, against which they had no resistance. The Maya preferred raiding and ambush to large-scale warfare, using spears, arrows and wooden swords with inset obsidian blades; the Xinca of the southern coastal plain used poison on their arrows. In response to the use of Spanish cavalry, the highland Maya took to digging pits and lining them with wooden stakes.

The Kaqchikel (also called Kachiquel) are one of the indigenous Maya peoples of the midwestern highlands in Guatemala. They constitute Guatemala's third largest Maya group. The name was formerly spelled in various other ways, including Cakchiquel, Kakchiquel, Caqchikel, and Cachiquel.

In Postclassic Maya times the capital of the main branch of the Kaqchikel was Iximché. Like the neighboring K'iche' (Quiché), they were governed by four lords: Tzotzil, Xahil, Tucuché and Acajal, who were responsible for the administrative, military and religious affairs. The Kakchikel recorded their history in the book Annals of the Cakchiquels, also known as Memorial de Sololá.The Chajoma were another Kaqchikel-speaking people; the ruins of Mixco Viejo have been identified as their capital.

Iximché was conquered by the Spanish conquistador Pedro de Alvarado in 1524. At that time, the Kaqchikel were the enemies of the neighbouring K'iche' Kingdom, and helped the Spaniards to conquer it. The first colonial capital of Guatemala, Tecpán Guatemala, was founded near Iximché on July 25, 1524. On November 22, 1527, after several Kaqchikel uprisings, the capital was moved to Ciudad Vieja, near Antigua Guatemala.

The Kaqchikel language, one of the Mayan languages, is spoken today by 400,000 people. They are largely subsistence farmers, and their culture reflects a fusion of Maya and Spanish influences.