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The area was long inhabited by the Tongva people (or "People of the Earth"), who were later renamed the Gabrieleños by the Spanish missionaries, after the nearby Mission San Gabriel Arcángel.

In 1798, José María Verdugo, a corporal in the Spanish army from Baja California, received the Rancho San Rafael from Governor Diego de Borica, formalizing his possession and use of land on which he had been grazing livestock and farming since 1784. Rancho San Rafael was a Spanish concession, of which 25 were made in California. Unlike the later Mexican land grants, the concessions were similar to grazing permits, with the title remaining with the Spanish crown.

In 1860, his grandson Teodoro Verdugo built the Catalina Verdugo Adobe, which is the oldest building in Glendale. The property is the location of the Oak of Peace, where early Californio leaders including Pio Pico met in 1847 and decided to surrender to Lieutenant Colonel John C. Frémont.

Verdugo's descendants sold the ranch in various parcels, some of which are included in present-day Atwater Village, Eagle Rock, and Highland Park neighborhoods of Los Angeles.

In 1884, residents gathered to form a townsite and chose the name "Glendale" (it was bounded by First Street (now Lexington Drive) on the north, Fifth Street (now Harvard Street) on the south, Central Avenue on the west, and the Childs Tract on the east. Residents to the southwest formed "Tropico" in 1887.

The Pacific Electric Railway brought streetcar service in 1904.^{[citation needed]}

Glendale incorporated in 1906, and annexed Tropico 12 years later. An important civic booster of the era was Leslie Coombs Brand (1859–1925), who built an estate in 1904 called El Miradero, featuring an eye-catching mansion, the architecture of which combined characteristics of Spanish, Moorish, and Indian styles, copied from the East Indian Pavilion at the 1893 World's Columbian Exposition held in Chicago, which he visited. Brand loved to fly, and built a private airstrip in 1919 and hosted "fly-in" parties, providing a direct link to the soon-to-be-built nearby Grand Central Airport. The grounds of El Miradero are now city-owned Brand Park and the mansion is the Brand Library, according to the terms of his will. Brand partnered with Henry E. Huntington to bring the Pacific Electric Railway, or the "Red Cars", to the area. Today, he is memorialized by one of the city's main thoroughfares, Brand Boulevard.

The city's population rose from 13,756 in 1920 to 62,736 in 1930. The Forest Lawn Cemetery opened in 1906 and was renamed Forest Lawn Memorial-Park in 1917. Pioneering endocrinologist and entrepreneur Henry R. Harrower opened his clinic in Glendale in 1920, which for many years was the largest business in the city. The American Green Cross, an early conservation and tree preservation society, was formed in 1926 (it disbanded three years later and the current organization of that name is unrelated).

Grand Central Airport was the departure point for the first commercial west-to-east transcontinental flight flown by Charles Lindbergh.

Until as late as the 1960s, Glendale was a sundown town. Nonwhites were required to leave city limits by a certain time each day or risk arrest and possible violence. In the 1930s, Glendale and Burbank prevented the Civilian Conservation Corps from stationing African American workers in a local park, citing sundown town ordinances that both cities had adopted. In 1964, Glendale was selected by George Lincoln Rockwell to be the West Coast headquarters of the American Nazi Party. After a legal battle with the city of Glendale, the party move their headquarters to El Monte in 1966.

Glendale began its historic preservation program in 1977 with the designation of 28 properties as city landmarks. In 1997, the program evolved with the establishment of the Glendale Register of Historic Resources. The register now has over 100 properties. In addition, 11 properties in Glendale are listed on the National Register of Historic Places. The city's most honored historic properties include the Catalina Verdugo Adobe, Brand Library & Art Center, Glendale Southern Pacific Railroad Depot, Grand Central Air Terminal, and Alex Theatre.

The 2010 United States Census reported that Glendale had a population of 191,719. According to the Southern California Association of Government's 2016 Demographic and Growth Forecast, the population of Glendale is expected to reach about 214,000 by 2040, an increase of about 11 percent from 2012. The population density was 6,268.6 people per square mile (2,420.3/km²). The racial makeup of Glendale was 136,226 (71.1%) White, 2,573 (1.3%) Black, 531 (0.3%) Native American, 31,434 (16.4%) Asian (6.9% Filipino, 5.4% Korean, 1.3% Chinese), 122 (0.1%) Pacific Islander, 12,146 (6.3%) from other races, and 8,687 (4.5%) from two or more races. Hispanics or Latinos of any race were 33,414 persons (17.4%). Non-Hispanic Whites were 61.5% of the population.

The census reported that 190,290 people (99.3% of the population) lived in households, 223 (0.1%) lived in noninstitutionalized group quarters, and 1,206 (0.6%) were institutionalized. Of the 72,269 households, 21,792 (30.2%) had children under the age of 18 living in them, 37,486 (51.9%) were opposite-sex married couples living together, 8,908 (12.3%) had a female householder with no husband present, 3,693 (5.1%) had a male householder with no wife present, 2,359 (3.3%) were unmarried opposite-sex partnerships, and 605 (0.8%) were same-sex married couples or partnerships. About 18,000 households (24.9%) were made up of individuals, and 7,077 (9.8%) had someone living alone who was 65 years of age or older. The average household size was 2.63. The 50,087 families (69.3% of all households) had an average family size of 3.19.

In the city, the population was distributed as 35,732 (18.6%) under the age of 18, 16,609 (8.7%) aged 18 to 24, 54,518 (28.4%) aged 25 to 44, 54,942 (28.7%) aged 45 to 64, and 29,918 (15.6%) who were 65 years of age or older. The median age was 41.0 years. For every 100 females, there were 91.1 males. For every 100 females age 18 and over, there were 87.9 males.

The 76,269 housing units averaged 2,493.8 per square mile (962.8/km²), of which 27,535 (38.1%) were owner-occupied, and 44,734 (61.9%) were occupied by renters. The homeowner vacancy rate was 1.3%; the rental vacancy rate was 5.5%; 76,769 people (40.0% of the population) lived in owner-occupied housing units and 113,521 people (59.2%) lived in rental housing units.

During 2009–2013, Glendale had a median household income of $53,020, with 14.2% of the population living below the federal poverty line.

As of the census of 2000, there were 194,973 people, 71,805 households, and 49,617 families residing in the city. The population density was 6,362.2 inhabitants per square mile (2,456.1/km²). There were 73,713 housing units averaged 2,405.3 per square mile (928.6/km²). The racial makeup of the city was 63.6% White, 1.6% Black, 0.3% Native American, 16.1% Asian American, 0.1% Pacific Islander, 8.6% from other races, and 10.1% from two or more races. About 19.7% of the population was Hispanic or Latino of any race.

Of the 71,805 households, 32.9% had children under the age of 18 living with them, 52.3% were married couples living together, 11.8% had a female householder with no husband present, and 30.9% were not families; 25.7% of all households were made up of individuals, and 8.7% had someone living alone who was 65 years of age or older. The average household size was 2.68 and the average family size was 3.27.

In the city, the population was distributed as 22.4% under the age of 18, 8.4% from 18 to 24, 32.2% from 25 to 44, 23.1% from 45 to 64, and 13.9% who were 65 years of age or older. The median age was 38 years. For every 100 females, there were 91.3 males. For every 100 females age 18 and over, there were 88.0 males.

The median income for a household in the city was $41,805, and for a family was $47,633. Males had a median income of $39,709 versus $33,815 for females. The per capita income for the city was $22,227. About 13.6% of families and 15.5% of the population were below the poverty line, including 20.7% of those under age 18 and 11.9% of those age 65 or over.

In June 2000, Erin Texeira of the Los Angeles Times stated that according to data from the US Census and the City of Glendale, the populations were about 30% Armenians, 25% other White, 25% Latino and Hispanic, and 16% Asian.

Glendale has one of the largest communities of Armenian descent in the United States.

Armenian families have lived in the city since the 1920s, but the surge in immigration escalated in the 1970s. Armenian Americans are well integrated into the city, with many businesses, several Armenian schools, and ethnic/cultural organizations serving this ethnic group. Most of the Armenians in Glendale arrived in the city in the past two decades. The city of Glendale is home to one of the largest Armenian communities outside of Armenia.

Beginning in the late 1980s, with assistance from family and friends already there, Armenians from the former Soviet Union began arriving. In the Glendale Unified School District, by 1988, along with students from the Middle East, they had become the largest ethnic group in the public schools, now having a larger number than the Latinos. Glendale became the municipality with the largest number of ethnic Armenians outside of Yerevan, Armenia. In 2014, a Glendale Police Department spokesperson, stated, "In five to eight years, the [Armenian] community went from a few thousand to about 40,000." Levon Marashlian, an instructor of Armenian history at Glendale College, stated that in the early 1990s Glendale's Armenian community became the largest in the Los Angeles metropolitan area, surpassing the Armenian community of Hollywood. Alice Petrossian, the GUSD director of intercultural education, stated that Burbank lies within the middle of other Armenian communities, so it attracted Armenians. There are also a great number of Armenian immigrants from Iran who, due to the religious restrictions and lifestyle limitations of the Islamic government, immigrated to the US, many to Glendale since it was where their relatives resided.

A new headquarters of the Armenian National Committee/Western Region opened in 1994. By 1999, about 25% of the population spoke Armenian and there were many Armenian businesses. By 2005 the Armenian population was 40% of the total population.

According to the United States 2000 Census, Glendale is home to 65,343 Armenian-Americans (making up 34.1% of the total population), increasing from 1990 when there were 31,402 Armenian-Americans in the city. As of 2005, one-third of Los Angeles' estimated 153,000 Armenians, or 51,000 around a quarter of Glendale's 205,000 residents was Armenian. At that time, Armenians held a majority on the Glendale city council, and it had done so since that year.

As of March 2018, four of the five members of Glendale's city council are of Armenian descent: Mayor Vartan Gharapetian and councilmembers Zareh Sinanyan (mayor from 2014 to 2015), Ara Najarian (mayor from 2007 to 2008, 2010 to 2011, and 2015 to 2016), and Vrej Agajanian. Former Armenian-American mayors of Glendale include Larry Zarian, Bob Yousefian, and Rafi Manoukian.

Singer Serj Tankian and bassist Shavo Odadjian, members of the Armenian-American rock band System of a Down, were based in Glendale at the time of formation.

The Cathedral of Saint Gregory the Illuminator, which is the seat of North American diocese of the Armenian Catholic Church, is located in Glendale. The Bishop of the Diocese, Rt. Rev. Mikaël Antoine Mouradian, is also resident in Glendale.

The Mexican American community was established in Glendale by the 1960s. The late 1980s and the early 1990s also saw increases in Mexican American population as Glendale offers a safer suburban environment away from the city with higher quality education. As of 2012, Filipino Americans were the third largest minority group in Glendale, making up seven percent of the city's total population, overtaking Korean Americans. After the Iranian Revolution, many Persians migrated to the cities seeking a suburban city with lower crime and quality education.

In 1977 and 1978, 10 murdered women were found in and around Glendale in what became known as the case of the Hillside Strangler. The murders were the work of Kenneth Bianchi and Angelo Buono, the latter of whom resided at 703 East Colorado Street, where most of the murders took place.

In 2014, Glendale was named the ninth-safest city in America in a report published by 24/7 Wall Street based on violent crime rates in cities with more than 100,000 people. Also in 2014, real estate company Movoto used FBI data crime data from 2013 to conduct a study of 100 U.S. cities with populations between 126,047 and 210,309 residents and concluded that Glendale was the safest mid-sized city in America.