Mission San Diego de Alcalá began on 16 July 1769, when Franciscan Junípero Serra founded the first of Spain's twenty-one Alta California missions near the San Diego presidio and the Kumeyaay village of Kosa'aay. The foundation supported Spanish claims on the Pacific coast as well as Catholic evangelization. Missionaries depended on Indigenous knowledge and labor while seeking to reorganize Kumeyaay religion, residence, work, and family life. The mission system therefore combined worship and settlement with colonial discipline and territorial expansion.

Poor soil, limited water, and tension with soldiers led the mission to move inland to its present location in 1774. Kumeyaay people built fields, irrigation works, workshops, residences, and churches under Franciscan direction. In November 1775, people from several Kumeyaay communities attacked and burned the mission, killing Father Luís Jayme and others. Spanish authorities rebuilt it with stronger defenses. The revolt reveals that Indigenous communities actively resisted demands, punishment, disease, cultural suppression, and the mission's growing occupation of their land.

The complex expanded during the late eighteenth and early nineteenth centuries, using adobe, timber, tile, and a distinctive bell wall. Livestock and agriculture supported the institution, while baptized Kumeyaay residents experienced crowded conditions and high mortality. Mexico secularized the California missions in the 1830s, transferring lands and disrupting the community. The property passed through private and governmental uses. United States troops occupied the buildings after the Mexican-American War, and long neglect left much of the church and quadrangle in ruins.

Catholic ownership was restored in the nineteenth century, but the appearance seen today owes much to twentieth-century reconstruction. Father Antonio Ubach and later restorers revived the site, and major work in the 1930s and 1940s recreated the church and campanario using historical evidence, surviving foundations, and idealized mission forms. It became a parish and was designated a minor basilica in 1976. Archaeological remains, museum displays, gardens, and reconstructed architecture now occupy the complex.

Mission San Diego should not be interpreted only as California's picturesque first mission. Its history begins in a Kumeyaay homeland and includes coercive conversion, labor, disease, resistance, and dispossession alongside religious devotion and later parish life. Much visible fabric is restored or reconstructed rather than untouched eighteenth-century work, so authenticity resides partly in location, surviving foundations, collections, and continued use. Responsible interpretation connects the basilica's colonial role with Kumeyaay endurance and presents reconstruction itself as part of the site's modern history and evolving regional public memory today.