The Santa Cruz River valley was home to O'odham communities whose farming, trade, language, and ceremonial life long preceded European colonization. Jesuit missionary Eusebio Francisco Kino entered the region in 1691 and established a mission presence at the O'odham village of Tumacácori. Missionization joined religious instruction with Spanish imperial control, livestock, new crops, labor demands, and settlement reorganization. O'odham people negotiated, adopted, resisted, and reshaped these changes while epidemics, raiding, and colonial violence altered communities across the borderlands of present-day Arizona and Sonora.

The first mission church stood at a location different from the visible ruin. After the Jesuits were expelled from Spanish territories in 1767, Franciscans assumed responsibility and moved the mission center to the present site. Construction of the surviving church began around 1800 under Fray Narciso Gutiérrez and continued intermittently. O'odham and other Indigenous workers, artisans from Mexico, and mission residents raised thick adobe walls, formed fired-brick details, carved and painted decoration, and built a convento, granary, cemetery, mortuary chapel, orchards, fields, and irrigation works.

War for Mexican independence disrupted supply and staffing, and the ambitious church was never fully completed as designed. Mexico secularized missions in the 1820s and expelled Spanish-born friars. Apache raiding, regional conflict, disease, and economic instability contributed to Tumacácori's abandonment by its remaining residents in 1848, who carried sacred objects to San Xavier del Bac. The United States acquired the area through the Gadsden Purchase in 1854. Travelers, settlers, treasure seekers, weather, and reuse then stripped roofs, beams, furnishings, and plaster from the empty complex.

Federal protection began when President Theodore Roosevelt created Tumacácori National Monument in 1908. Preservation crews stabilized the church's original adobe core, rebuilt protective roof sections, capped walls, repaired plaster, and reconstructed limited architectural elements. A museum and visitor center designed in a Spanish Colonial Revival idiom opened in 1937; it is a New Deal interpretation of regional architecture, not a surviving mission building. Congress expanded and redesignated the park in 1990 to include the Guevavi and Calabazas mission sites, which remain primarily archaeological landscapes with limited guided access.

The National Park Service manages Tumacácori in consultation with O'odham communities and other associated peoples. Admission, tours, and access to outlying units follow current schedules. The main church is an authentic early nineteenth-century ruin, but its standing surfaces combine historic adobe and masonry with generations of stabilization and replacement sheltering; missing roofs and interiors have not been fully recreated. Interpretation should distinguish the mission's architectural beauty from the colonial system that produced it. Tumacácori records Indigenous persistence, Catholic devotion, coerced change, skilled labor, borderland movement, abandonment, archaeology, and the continuing challenge of preserving earthen walls.