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Spanish period

The first European to visit the region was explorer Juan Rodríguez Cabrillo, sailing under the flag of Castile but possibly born in Portugal. Sailing his flagship San Salvador from Navidad, New Spain, Cabrillo claimed the bay for the Spanish Empire in 1542, and named the site "San Miguel". In November 1602, Sebastián Vizcaíno was sent to map the California coast. Arriving on his flagship San Diego, Vizcaíno surveyed the harbor and what are now Mission Bay and Point Loma and named the area for the Catholic Saint Didacus, a Spaniard more commonly known as San Diego de Alcalá. On November 12, 1602, the first Christian religious service of record in Alta California was conducted by Friar Antonio de la Ascensión, a member of Vizcaíno's expedition, to celebrate the feast day of San Diego.

The permanent European colonization of both California and San Diego began in 1769 with the arrival of four contingents of Spaniards from New Spain and the Baja California peninsula. Two seaborne parties reached San Diego Bay: the San Carlos, under Vicente Vila and including as notable members the engineer and cartographer Miguel Costansó and the soldier and future governor Pedro Fages, and the San Antonio, under Juan Pérez. An initial overland expedition to San Diego from the south was led by the soldier Fernando Rivera and included the Franciscan missionary, explorer, and chronicler Juan Crespí, followed by a second party led by the designated governor Gaspar de Portolà and including the mission president (and now saint) Junípero Serra.

In May 1769, Portolà established the Fort Presidio of San Diego on a hill near the San Diego River above the Kumeyaay village of Cosoy, which would later become incorporated into the Spanish settlement, making it the first settlement by Europeans in what is now the state of California. In July of the same year, Mission San Diego de Alcalá was founded by Franciscan friars under Serra. The mission became a site for a Kumeyaay revolt in 1775, which forced the mission to relocate six miles (10 km) up the San Diego River. By 1797, the mission boasted the largest native population in Alta California, with over 1,400 neophytes living in and around the mission proper. Mission San Diego was the southern anchor in Alta California of the historic mission trail El Camino Real. Both the Presidio and the Mission are National Historic Landmarks.