Located in present-day San Diego, California, it was founded on July 16, 1769, by Spanish friar Junípero Serra, in an area long inhabited by the Kumeyaay people.

Father Luis Jayme, California's first Christian martyr who was among those killed during the 1775 uprising against the mission,[19] lies entombed beneath the chancel floor.

The former Spanish settlement at the Kumeyaay Nipawai lies within that area occupied during the late Paleoindian period and continuing into the present day by the Native society commonly known as the Diegueño;[20] the name denotes those people who were ministered by the padres at Mission San Diego de Alcalá.

Some sixty years later another Spanish explorer, Sebastián Vizcaíno, made landfall some ten miles from the present Mission site.

However, it was not until 1741—the time of the Vitus Bering expedition, when the territorial ambitions of Tsarist Russia towards North America became known—that King Philip V felt such installations were necessary for Upper California.

[30] An estimated 800 "American Indians" pillaged the mission, burned it to the ground and massacred a blacksmith, a carpenter (mortally wounded), and Father Jayme, who became California's first Catholic Martyr.

[19] Survivors of the night-long attack were one corporal and three Leather Jacket soldiers, one blacksmith, two children who were the son and nephew of the Presidio commandant, and Associate Pastor Father Vicente Fuster.

[19] However, the scarce amount of water and the difficulty of making the land until[19] (feasible for preparing crops to be planted by plowing and fertilizing) [31] made the re-establishment of the mission a long and difficult process.

On June 8, 1846, Mission San Diego de Alcalá was given to Santiago Argüello by Governor Pío Pico "for services rendered to the government.

Before the establishment of the missions, the native peoples knew how to utilize bone, seashells, stone, and wood for building, tool making, weapons, and much more.

Everything consumed and otherwise utilized by the natives was produced at the missions under the supervision of the padres; thus, the neophytes not only supported themselves, but after 1811 sustained the entire military and civil government of California.

[38] Wheat, corn, wine grapes, barley, beans, cattle, horses, and sheep were the major crops at San Diego.