Mission Indians was a term used to refer to the Indigenous peoples of California who lived or grew up in the Spanish mission system in California. Today the term is used to refer to their descendants and to specific, contemporary tribal nations in California.

Spanish explorers arrived on California's coasts as early as the mid-16th century. In 1769, the first Spanish Franciscan mission was built in San Diego. Local tribes were relocated and conscripted into forced labor on the mission, stretching from San Diego to San Francisco. Disease, starvation, excessive physical labor, and torture decimated these tribes. Many were baptized as Catholics by the Franciscan missionaries at the missions.

Mission Indians were from many regional Native American tribes; their members were often relocated together in new mixed groups, and the Spanish named the Indian groups after the responsible mission. For instance, the Payomkowishum were renamed Luiseños, after the Mission San Luis Rey; the Acjachemem were renamed the Juaneños, after the Mission San Juan Capistrano and the Kizh or Kisiannos renamed the Gabrieleño, after the Mission San Gabriel.

The Catholic priests forbade the Indians from practicing their native culture, resulting in the disruption of many tribes' linguistic, spiritual, and cultural practices. With no acquired immunity to the exposure of European diseases (as well as sudden cultural upheaval and lifestyle demands), the population of Mission Indians suffered high mortality and dramatic decreases, especially in the coastal regions; the population was reduced by 90 percent, between 1769 and 1848.

Despite the missionaries' attempts to convert the Indigenous peoples of the missions, often referred to in mission records as "neophytes", they indicated that their attempts at conversion were often unsuccessful. Indigenous groups did not passively assimilate into mission life under Spanish authority. Archaeological evidence proposes that Indigenous people maintained and adapted their cultural practices through food preparation and household organization.

Indigenous worldviews and communal structures continued under colonial rule. Native communities reinterpreted newly imposed systems to preserve sacred fundamental components such as kinship networks through spiritual and cultural continuity despite the Catholic restrictions put upon them. Indigenous Californians maintained relationships with kinship networks outside of the mission communities, which continued their cultural knowledge across generations even after mission imposition. Archaeological evidence suggests that previously formed trade networks and political structures further developed despite colonial disruption.

Leaders of Indigenous tribes negotiated their cooperation within colonial institutions with mission padres as a form of resistance. Resistance to the Spanish mission system was represented through overt defiance, strategic disengagement, and refusal to participate in the forced labor needed to maintain the missions. Some Native tribes fled the missions and relocated to mountainous areas unfamiliar to the Spanish as a means to continue their traditional lifestyle. The refusal to adopt the Spanish language and religious practices was another way to resist assimilation.

For example, in 1803, twenty-eight years into the mission period, Friar Fermín de Lasuén wrote: