The first European to visit the region was Portuguese explorer Juan Rodríguez Cabrillo, (1499 - 1543), who sailed his flagship, the San Salvador, from Navidad, New Spain. Cabrillo claimed the bay for the Spanish Empire and named the site San Miguel. In November of 1602, Sebastián Vizcaíno (1548-1624) was sent to map the California coast. He arrived with his flagship "San Diego". Vizcaíno surveyed the harbor and what is now Mission Bay and Point Loma, naming the area for the Spanish Catholic Saint St. Didacus (More commonly known as San Diego). On November 12, 1602, the first Christian religious service of record in Alta California was conducted by Fray Antonio de la Ascensión, a member of Vizcaíno's expedition, to celebrate the feast day of San Diego.
In 1769, the Presidio of San Diego (military post), which overlooks Old Town, was established by Gaspar de Portolà at almost the same time as Mission San Diego de Alcalá was founded by the Franciscan friars led by Father Junípero Serra. By 1797, the mission boasted the largest native population in Alta California (over 1,400 neophytes lived in and around the mission proper). After New Spain won its independence from the Spanish Empire in 1823, Mission San Diego de Alcalá's fortunes declined in the 1830s after the decree of secularization was enacted, as was the case with all of the missions under the control of Mexico. In 1847 San Diego was a destination of the 2000 mile march of the Mormon Battalion which built the city's first courthouse with brick.
After the Battle of San Pasqual, the end of the Mexican-American War and the gold rush of 1848, San Diego was designated the seat of the newly-established San Diego County and was incorporated as a city in 1850. In the years before World War I, the anti-capitalist labor union the Industrial Workers of the World conducted a free speech fight in San Diego, and was met with a brutal response.
Significant U.S. Naval presence began in 1907 with the establishment of the Navy Coaling Station, which gave further impetus to the development of the town. San Diego hosted two World's Fairs, the Panama-California Exposition in 1915 and the California Pacific International Exposition in 1935. Many of the Spanish/Baroque-style buildings in the city's Balboa Park were built for these expositions (especially for the one in 1915). Intended to be temporary structures, most remained in continuous use until they progressively fell into disrepair. All were eventually rebuilt using castings of the original facades to faithfully retain the architectural style.

After World War II, the military played an increasing role in the local economy. But at the end of the Cold War the local economy experienced a downturn due to cutbacks in the local defense and aerospace industry. San Diego leaders sought to diversify the city's economy, and San Diego has since become a major center of the emerging biotech industry.

Downtown San Diego has been enjoying an urban renewal since the 1980s, beginning with the opening of Horton Plaza, the revival of the Gaslamp Quarter, and the construction of the San Diego Convention Center. The Centre City Development Corporation (CCDC), San Diego's downtown redevelopment agency, has transformed what was a largely abandoned downtown into a glittering showcase of waterfront skyscrapers, live-work loft developments, five-star hotels, and many cafes, restaurants, and shops.
The North Embarcadero is slated to have parks in addition to a waterfront promenade. And Balboa Park will be linked to downtown with a view corridor. The recent boom in the construction of condos and skyscrapers has brought with it a gentrification frenzy, and some people are concerned that speculators have played too big a role in the condo market downtown. In the meantime, the city is committed to a "smart growth" development scheme that would increase density along transit corridors in older neighborhoods (the "City of Villages" planning concept.) Some neighborhoods are resisting this planning approach. But "mixed-use development" has had its successes, especially the award-winning Uptown Shopping Center in Hillcrest.

The latest accomplishment of CCDC has been the recent inauguration of PETCO Park. The once-industrial East Village adjacent to the new ballpark is now the new frontier in San Diego's downtown urban renewal.