Over its history, the Jalisco area has been occupied by a variety of ethnicities including the Bapames, Caxcans, Cocas, Cuachilchils, Huichols, Cuyutecos, Otomis, Nahuas, Tecuejes, Tepehuans, Tecos, P’urhépechas, Pinomes, Tzaultecas and Xilotlantzingas. Some writers have also mentioned groups such as the Pinos, Otontlatolis, Amultecas, Coras, Xiximes, Tecuares, Tecoxines and Tecualmes. When the Spanish arrived the main ethnic groups were the Cazcanes, who inhabitd the northern regions near Teocalteche and the Lagos de Morenos and the Huichols, who also inhabited the northwest near Huejúcar and Colotlán. Other groups included the Guachichil in the Los Altos area, the Nahuatl speaking Cuyutecos in the west, the Tecuexes and Cocas near what is now Guadalajara and the Guamares in the east near the Guanajuato border.

Shortly after the conquest of the Aztecs in 1521, the Spanish pushed west. They overpowered the P’urepécha in Michoacán, converting their capital of Tzintzuntzan as a base to move further west. One reason for the push towards the Pacific was to build ships and shipping facilities in order to initiate trade with Asia. Another draw was to find more mineral wealth as the P’urépecha had already developed copper working along with silver and gold.

In 1522, Cristóbal de Olid was sent by Hernán Cortés northwest from Mexico City into Jalisco. Other incursions were undertaken by Alonso de Avalos and Juan Alvarez Chico in 1521, Gonzalo de Sandoval in 1522 and Francisco Cortés de San Buenaventura in 1524. The first area explored now belongs to the south of Jalisco down into what it now the state of Colima. In 1529, the president of the First Audencia in New Spain, Nuño de Guzmán came west from Mexico City with a force of 300 Spanish and 6,000 Indian allies, traveling through Michoacán, Guanajuato, Jalisco and Sinaloa. At the end of 1531, Guzmán founded the Villa del Espíritu Santo de la Mayor Españas as the capital of the newly conquered western lands. The name was changed shortly thereafter to Santiago Galicia de Compostela. In 1531, Guzmán ordered his chief lieutenant, Cristóbal de Oñate to found the Villa of Guadalajara, named after Guzmán’s hometown in Spain. It was initially founded in what is now Nochistlán in Zacatecas. Construction began in 1532, but the small settlement came under repeated attacks from the Cazcanes until it was abandoned in 1533. The town of Guadalajara would move four times in total before coming to its modern site in 1542.

Most of Jalisco was conquered by Nuño de Guzmán, who then sent expeditions from there into Zacatecas and Aguascalientes in 1530. The first encomiendas were granted to the Spanish conquistadors in Nueva Galicia by Nuño de Guzmán and later by Antonio de Mendoza. Nuño de Guzmán founded five Spanish settlements, San Miguel, Chiametla, Compostela, Purificación, and Guadalajara to form the first administrative structure of the area. However, most of these settlements were too small to support the grand plans of many Spanish in America and attracted few settlers. By the end of the early colonial period, all of these settlements either disappeared or were moved to other locations. Guzmán was named the first governor of the region and Franciscans established monasteries in Tetlán and Ajijic.

Guzmán was brutal to the local indigenous populations, sending many to slavery in the Caribbean and committing genocide in areas. This would eventually lead to his imprisonment in 1536 by viceroy Antonio de Mendoza. However, not only Guzmán was to blame for subsequent indigenous hostility. The Spanish in Guadalajara and other locations began to take indigenous peoples as slaves in 1543. These Spanish in the area were looking to enrich themselves as fast as possible, following the success of the same of those who arrived first to the Mexico City area. This led to abuses of the native populations, widespread corruption and confrontations between the Spanish and the indigenous and among the Spanish themselves. Overwork and disease reduced the native population by about ninety percent between 1550 and 1650.

This would begin a history of conflict and uprising in the Jalisco area which would last from the 16th century to the 1920s. Early uprisings include that in Culiacán in 1533, of the Coaxicoria in 1538 and the Texcoixines and Caxcanes in 1541. Subduing the indigenous peoples proved difficult in general due to a lack of large dominion to co-opt as was done in the Mexico City area. In the early colonial period, it was not certain that the Spanish could impose its language or culture onto the native population. The initial effect of colonization was the influence of Nahuatl, as mestizos and indigenous from central Mexico had a greater impact on the local populations than the sparse Spanish.

The most significant early revolt was the Mixtón Rebellion in 1541. United under a leader named Tenamaxtli, the indigenous of the Jalisco area laid siege to Guadalajara. The Spanish provincial government under Oñate could not withstand the assault and Pedro de Alvarado was sent to area from Mexico City but this initial attempt was thwarted. During a battle, a horse fell on Alvarado, mortally wounding him. Viceroy Mendoza then arrived with a force of 300 horsemen, 300 infantry, artillery and 20,000 Tlaxcalan and Aztec allies to recapture the territory held by the indigenous resistance. The Mixtón War prompted Charles V to create the Audencia of Nueva Galicia which extended from Michoacán and into the present states of Jalisco, Colima, and parts of Zacatecas, Durango and Sinaloa. An Indian Council was formed to advise the four members of the new Spanish government. The area was called Nueva Galicia because the Crown wanted to reproduce in the new lands a territory similar to that of Spain. The seat of this colony was moved to Guadalajara in 1561, and it was made independent of Mexico City in 1575.

Most of the evangelization fell to regular clergy instead of monks. The bishopric of Guadalajara was established by Pope Paul II in 1546.

The Chichimeca War began in 1550. In 1554, the Chichimecas attacked a Spanish caravan of sixty wagons at the Ojuelos Pass, carrying off 30,000 pesos of clothing, silver and other valuables. At the end of the century, the Spanish were able to negotiate a peace with most. There later uprisings such as in Guaynamota in 1584, in Acaponeta in 1593, one led by Cogixito in 1617, and one in Nostic in 1704. The last major colonial era insurrection occurred in 1801 led by an indigenous named Mariano. The last of the Chichimeca groups were ultimately defeated in 1591. However, these uprisings would gradually be overshadowed by the consolidation of political and economic power and peace treaties negotiated with indigenous groups such as the Coras and indigenous groups such as the Otomi were brought to settle.

The province of Jalisco was separated from Michoacán in 1607 with the name of Santiago.

Despite these conflicts, the 17th and 18th centuries brought development and economic prosperity to the region. In the colonial period, Guadalajara grew as the center of an agricultural and cattle produing area. Guadalajara grew from about 6,000 people in 1713 to 20,000 in mid century to 35,000 at the beginning of the 19th century. The region’s ceramic tradition began in the early colonial period, with native traditions superimposed by European ones. The center of ceramic production was Tonalá due to its abundance of raw materials. The Guadalajara tradition became famous enough for wares to be exported to other parts of New Spain and Europe. The area was also important to the commerce of New Spain, as its strategic location funneled imported goods to other parts of the colony.

In 1786, New Spain was reorganized into twelve “intendencias” and three provinces. The Intendencia of Guadalajara included what is now Jalisco, Aguascalientes, Nayarit and Colima. Aguascalientes was separated from Jalisco in 1789.

The University of Guadalajara was founded in 1792.