The original inhabitants of the region are now known as the San Dieguito and La Jolla people. The Kumeyaay people migrated into the area of San Diego around 1000 CE, who erected villages scattered across the region, including the village of Cosoy (Kosa'aay) which was the Kumeyaay village that the future settlement of San Diego would stem from in today's Old Town. The village of Cosoy was made up of thirty to forty families living in pyramid-shaped housing structures and was supported by a freshwater spring from the hillsides.

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 California and of 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 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.

In 1821, Mexico won its independence from Spain, and San Diego became part of the Mexican territory of Alta California. In 1822, Mexico began its attempt to extend its authority over the coastal territory of Alta California. The fort on Presidio Hill was gradually abandoned, while the town of San Diego grew up on the level land below Presidio Hill. The Mission was secularized by the Mexican government in 1834, and most of the Mission lands were granted to former soldiers. The 432 residents of the town petitioned the governor to form a pueblo, and Juan María Osuna was elected the first alcalde ("municipal magistrate"), defeating Pío Pico in the vote. (See, List of pre-statehood mayors of San Diego.) However, San Diego had been losing population throughout the 1830s and in 1838 the town lost its pueblo status because its size dropped to an estimated 100 to 150 residents. Beyond town Mexican land grants expanded the number of California ranchos that modestly added to the local economy.

Americans gained an increased awareness of California, and its commercial possibilities, from the writings of two countrymen involved in the often officially forbidden, to foreigners, but economically significant hide and tallow trade, where San Diego was a major port and the only one with an adequate harbor: William Shaler's "Journal of a Voyage Between China and the North-Western Coast of America, Made in 1804" and Richard Henry Dana's more substantial and convincing account, of his 1834–36 voyage, the classic Two Years Before the Mast.

In 1846, the United States went to war against Mexico and sent a naval and land expedition to conquer Alta California. At first, they had an easy time of it, capturing the major ports including San Diego, but the Californios in southern Alta California struck back. Following the successful revolt in Los Angeles, the American garrison at San Diego was driven out without firing a shot in early October 1846. Mexican partisans held San Diego for three weeks until October 24, 1846, when the Americans recaptured it. For the next several months the Americans were blockaded inside the pueblo. Skirmishes occurred daily and snipers shot into the town every night. The Californios drove cattle away from the pueblo hoping to starve the Americans and their Californio supporters out. On December 1, the American garrison learned that the dragoons of General Stephen W. Kearney were at Warner's Ranch. Commodore Robert F. Stockton sent a mounted force of fifty under Captain Archibald Gillespie to march north to meet him. Their joint command of 150 men, returning to San Diego, encountered about 93 Californios under Andrés Pico. In the ensuing Battle of San Pasqual, fought in the San Pasqual Valley which is now part of the city of San Diego, the Americans suffered their worst losses in the campaign. Subsequently, a column led by Lieutenant Gray arrived from San Diego, rescuing Kearny's battered and blockaded command.

Stockton and Kearny went on to recover Los Angeles and force the capitulation of Alta California with the "Treaty of Cahuenga" on January 13, 1847. As a result of the Mexican–American War of 1846–48, the territory of Alta California, including San Diego, was ceded to the United States by Mexico, under the terms of the Treaty of Guadalupe Hidalgo in 1848. The Mexican negotiators of that treaty tried to retain San Diego as part of Mexico, but the Americans insisted that San Diego was "for every commercial purpose of nearly equal importance to us with that of San Francisco," and the Mexican–American border was eventually established to be one league south of the southernmost point of San Diego Bay, so as to include the entire bay within the United States.

The state of California was admitted to the United States in 1850. That same year San Diego has designated the seat of the newly established San Diego County and was incorporated as a city. Joshua H. Bean, the last alcalde of San Diego, was elected the first mayor. Two years later the city was bankrupt; the California legislature revoked the city's charter and placed it under control of a board of trustees, where it remained until 1889. A city charter was reestablished in 1889, and today's city charter was adopted in 1931.

The original town of San Diego was located at the foot of Presidio Hill, in the area which is now Old Town San Diego State Historic Park. The location was not ideal, being several miles away from navigable water at its port at La Playa. In 1850, William Heath Davis promoted a new development by the bay shore called "New San Diego", several miles south of the original settlement; however, for several decades the new development consisted only of a pier, a few houses and an Army depot for the support of Fort Yuma. After 1854, the fort became supplied by sea and by steamboats on the Colorado River and the depot fell into disuse. From 1857 to 1860, San Diego became the western terminus of the San Antonio-San Diego Mail Line, the earliest overland stagecoach and mail operation from the Eastern United States to California, coming from Texas through New Mexico Territory in less than 30 days.

In the late 1860s, Alonzo Horton promoted a move to the bayside area, which he called "New Town" and which became Downtown San Diego. Horton promoted the area heavily, and people and businesses began to relocate to New Town because its location on San Diego Bay was convenient to shipping. New Town soon eclipsed the original settlement, known to this day as Old Town, and became the economic and governmental heart of the city. Still, San Diego remained a relative backwater town until the arrival of a railroad connection in 1878.

In the early part of the 20th century, San Diego hosted the World's Fair twice: the Panama-California Exposition (1915) and the California Pacific International Exposition in 1935. Both expositions were held in Balboa Park, and many of the Spanish/Baroque-style buildings that were built for those expositions remain to this day as central features of the park. The buildings were intended to be temporary structures, but most remained in continuous use until they progressively fell into disrepair. Most were eventually rebuilt, using castings of the original façades to retain the architectural style. The menagerie of exotic animals featured at the 1915 exposition provided the basis for the San Diego Zoo. During the 1950s there was a citywide festival called Fiesta del Pacifico highlighting the area's Spanish and Mexican past. In the 2010s there was a proposal for a large-scale celebration of the 100th anniversary of Balboa Park, but the plans were abandoned when the organization tasked with putting on the celebration went out of business.

The southern portion of the Point Loma peninsula was set aside for military purposes as early as 1852. Over the next several decades the Army set up a series of coastal artillery batteries and named the area Fort Rosecrans. Significant U.S. Navy presence began in 1901 with the establishment of the Navy Coaling Station in Point Loma, and expanded greatly during the 1920s. By 1930, the city was host to Naval Base San Diego, Naval Training Center San Diego, San Diego Naval Hospital, Camp Matthews, and Camp Kearny (now Marine Corps Air Station Miramar). The city was also an early center for aviation: as early as World War I, San Diego was proclaiming itself "The Air Capital of the West". The city was home to important airplane developers and manufacturers like Ryan Airlines (later Ryan Aeronautical), founded in 1925, and Consolidated Aircraft (later Convair), founded in 1923.Charles A. Lindbergh's plane The Spirit of St. Louis was built in San Diego in 1927 by Ryan Airlines.

During World War II, San Diego became a major hub of military and defense activity, due to the presence of so many military installations and defense manufacturers. The city's population grew rapidly during and after World War II, more than doubling between 1930 (147,995) and 1950 (333,865). During the final months of the war, the Japanese had a plan to target multiple U.S. cities for biological attack, starting with San Diego. The plan was called "Operation Cherry Blossoms at Night" and called for kamikaze planes filled with fleas infected with plague (Yersinia pestis) to crash into civilian population centers in the city, hoping to spread plague in the city and effectively kill tens of thousands of civilians. The plan was scheduled to launch on September 22, 1945, but was not carried out because Japan surrendered five weeks earlier.

After World War II, the military continued to play a major role in the local economy, but post-Cold War cutbacks took a heavy toll on the local defense and aerospace industries. The resulting downturn led San Diego leaders to seek to diversify the city's economy by focusing on research and science, as well as tourism.

From the start of the 20th century through the 1970s, the American tuna fishing fleet and tuna canning industry were based in San Diego, "the tuna capital of the world". San Diego's first tuna cannery was founded in 1911, and by the mid-1930s the canneries employed more than 1,000 people. A large fishing fleet supported the canneries, mostly staffed by immigrant fishermen from Japan, and later from the Portuguese Azores and Italy whose influence is still felt in neighborhoods like Little Italy and Point Loma. Due to rising costs and foreign competition, the last of the canneries closed in the early 1980s.

Downtown San Diego was in decline in the 1960s and 1970s, but experienced some urban renewal since the early 1980s, including the opening of Horton Plaza, the revival of the Gaslamp Quarter, and the construction of the San Diego Convention Center; Petco Park opened in 2004.

The city had a population of 1,307,402 according to the 2010 census, distributed over a land area of 372.1 square miles (963.7 km²). The urban area of San Diego extends beyond the administrative city limits and had a total population of 2,956,746, making it the third-largest urban area in the state, after that of the Los Angeles metropolitan area and San Francisco metropolitan area. They, along with the Riverside–San Bernardino, form those metropolitan areas in California larger than the San Diego metropolitan area, which had a total population of 3,095,313 at the 2010 census.

The 2010 population represents an increase of just under 7% from the 1,223,400 people, 450,691 households, and 271,315 families reported in 2000. The estimated city population in 2009 was 1,306,300. The population density was 3,771.9 inhabitants per square mile (1,456.3/km²). The racial makeup of San Diego was 58.9% White, 6.7% African American, 0.6% Native American, 15.9% Asian (5.9% Filipino, 2.7% Chinese, 2.5% Vietnamese, 1.3% Indian, 1.0% Korean, 0.7% Japanese, 0.4% Laotian, 0.3% Cambodian, 0.1% Thai). 0.5% Pacific Islander (0.2% Guamanian, 0.1% Samoan, 0.1% Native Hawaiian), 12.3% from other races, and 5.1% from two or more races. The ethnic makeup of the city was 28.8% Hispanic or Latino (of any race); 24.9% of the total population were Mexican American, 1.4% were Spanish American and 0.6% were Puerto Rican. Median age of Hispanics was 27.5 years, compared to 35.1 years overall and 41.6 years among non-Hispanic whites; Hispanics were the largest group in all ages under 18, and non-Hispanic whites constituted 63.1% of population 55 and older.

As of January 2019, the San Diego City and County had the fifth-largest homeless population among major cities in the United States, with 8102 persons experiencing homelessness. In the city of San Diego, 4887 individuals were experiencing homelessness according to the 2020 count.

In 2000 there were 451,126 households, out of which 30.2% had children under the age of 18 living with them, 44.6% were married couples living together, 11.4% had a female householder with no husband present, and 39.8% were non-families. Households made up of individuals account for 28.0%, and 7.4% had someone living alone who was 65 years of age or older. The average household size was 2.61, and the average family size was 3.30.

The U.S. Census Bureau reported that in 2000, 24.0% of San Diego residents were under 18, and 10.5% were 65 and over. As of 2011 the median age was 35.6; more than a quarter of residents were under age 20 and 11% were over age 65.Millennials (ages 18 through 34) constitute 27.1% of San Diego's population, the second-highest percentage in a major U.S. city. The San Diego County regional planning agency, SANDAG, provides tables and graphs breaking down the city population into five-year age groups.

In 2000, the median income for a household in the city was $45,733, and the median income for a family was $53,060. Males had a median income of $36,984 versus $31,076 for females. The per capita income for the city was $35,199. According to Forbes in 2005, San Diego was the fifth wealthiest U.S. city, but about 10.6% of families and 14.6% of the population were below the poverty line, including 20.0% of those under age 18 and 7.6% of those age 65 or over. San Diego was rated the fifth-best place to live in the United States in 2006 by Money magazine, although it was no longer rated in the top 100 places by 2017. As of January 1, 2008 estimates by the San Diego Association of Governments revealed that the household median income for San Diego rose to $66,715, up from $45,733 in 2000.

San Diego was named the ninth-most LGBT-friendly city in the U.S. in 2013. The city also has the seventh-highest percentage of gay residents in the U.S. Additionally in 2013, San Diego State University (SDSU), one of the city's prominent universities, was named one of the top LGBT-friendly campuses in the nation.

According to a 2014 study by the Pew Research Center, 68% of the population of the city identified themselves as Christians, with 32% professing attendance at a variety of churches that could be considered Protestant, and 32% professing Roman Catholic beliefs. while 27% claim no religious affiliation. The same study says that other religions (including Judaism, Buddhism, Islam, and Hinduism) collectively make up about 5% of the population.