Spanish colonists established Guadalajara at several locations before fixing the city in the Atemajac Valley in 1542, on lands connected with Indigenous Caxcan, Tecuexe, and other communities violently drawn into colonial rule. A modest church became the first cathedral after the diocese was created, but fire damaged it in 1574. Construction of the present cathedral had begun in 1561 under royal authorization and advanced slowly with architect Martín Casillas and many craftspeople. The building was completed in the early seventeenth century and later consecrated as the city's principal Catholic church.

The cathedral's basilican interior, stone walls, chapels, sacristies, towers, artworks, burials, and liturgical furnishings accumulated under Spanish rule. It anchored an urban grid of plazas, government offices, convents, markets, and elite residences while Catholic institutions participated in conversion, education, charity, landholding, and colonial hierarchy. Guadalajara grew into the administrative and commercial center of western New Spain. Indigenous and mixed-race laborers, artisans, confraternities, merchants, clergy, women donors, and enslaved people all contributed to the city, although traditional monumental narratives often emphasize bishops, kings, and architects.

Earthquakes repeatedly transformed the cathedral. A major shock in 1818 brought down the original towers and damaged the dome; replacement structures suffered further damage in 1849. Architect Manuel Gómez Ibarra designed the distinctive neo-Gothic spires, completed in the 1850s with colored tile covering. Later earthquakes in the twentieth and twenty-first centuries required continuing structural assessment and repair. Surrounding civic projects also changed the center: streets widened, buildings disappeared, and large plazas created a more open monumental setting that differs from the denser colonial city.

Substantial sixteenth- and seventeenth-century masonry, plan, chapels, art, and interior fabric survive, but the towers and portions of the dome are nineteenth-century reconstructions after seismic loss. Stone replacement, reinforcement, repaired vaults, renewed roofing, restored art, lighting, sound, security, and visitor controls represent later work. The broader historic center includes genuine colonial and republican buildings, altered façades, modern infill, reconstructed streetscapes, and contemporary public spaces. It should not be described as a uniformly preserved sixteenth-century district or the cathedral as architecturally unchanged since completion.

The Archdiocese of Guadalajara uses and administers the active cathedral, while federal, state, and municipal heritage authorities regulate protected monuments and public spaces. Worship, ceremonies, maintenance, and seismic safety take priority over tourism, and access varies accordingly. Interpretation should connect sacred art and urban beauty with colonization, Indigenous resistance, labor, earthquakes, independence, and metropolitan growth. The center's authenticity lies in a layered city and a cathedral repeatedly repaired after disaster. Explicitly dating the iconic spires and restored structural elements makes its endurance more accurate and compelling.