Santa Rosa was founded in 1833 and named after Saint Rose of Lima. Before the arrival of Europeans, the Santa Rosa Plain was home to a strong and populous tribe of Pomo natives known as the Bitakomtara. The Bitakomtara controlled the area closely, barring passage to others until permission was arranged. Those who entered without permission were subject to harsh penalties. The tribe gathered at ceremonial times on Santa Rosa Creek near present-day Spring Lake Regional Park. Upon the arrival of Europeans, the Pomos were decimated by smallpox brought from Europe. By 1900, the Pomo population had decreased by 95%.

The first known permanent European settlement of Santa Rosa was the homestead of the Carrillo family of California, in-laws to Mariano Guadalupe Vallejo, who settled the Sonoma pueblo and Petaluma area. In the 1830s, during the Mexican period, the family of María López de Carrillo built an adobe house on their Rancho Cabeza de Santa Rosa land grant, just east of what later became downtown Santa Rosa. Allegedly, however, by the 1820s, before the Carrillos built their adobe in the 1830s, Spanish and Mexican settlers from nearby Sonoma and other settlements to the south raised livestock in the area and slaughtered animals at the fork of the Santa Rosa Creek and Matanzas Creek, near the intersection of modern-day Santa Rosa Avenue and Sonoma Avenue. This is supposedly the origin of the name of Matanzas Creek as, because of its use as a slaughtering place, the confluence came to be called La Matanza.

By the 1850s, a Wells Fargo post and general store were established in what is now downtown Santa Rosa. In the mid-1850s, several prominent locals, including Julio Carrillo, son of Maria Carrillo, laid out the grid street pattern for Santa Rosa with a public square in the center, a pattern which largely remains as the street pattern for downtown Santa Rosa to this day, despite changes to the central square, now called Old Courthouse Square.

In 1867, the county recognized Santa Rosa as an incorporated city and in 1868 the state officially confirmed the incorporation, making it officially the third incorporated city in Sonoma County, after Petaluma, incorporated in 1858, and Healdsburg, incorporated in 1867.

The U.S. Census records, among others, show that after California became a state, Santa Rosa grew steadily early on, despite initially lagging behind nearby Petaluma in the 1850s and early 1860s. According to the U.S. Census, in 1870 Santa Rosa was the eighth largest city in California, and county seat of one of the most populous counties in the state. Growth and development after that was steady but never rapid. The city continued to grow when other early population centers declined or stagnated, but by 1900 it was being overtaken by many other newer population centers in the San Francisco Bay Area and Southern California. According to a 1905 article in the Press Democrat newspaper reporting on the "Battle of the Trains", the city had just over 10,000 people at the time.

The 1906 San Francisco earthquake essentially destroyed the entire downtown, but the city's population did not greatly suffer. However, after that period the population growth of Santa Rosa, as with most of the area, was very slow.

Famed director Alfred Hitchcock filmed his thriller Shadow of a Doubt in Santa Rosa in 1943; the film gives glimpses of Santa Rosa in the 1940s. Many of the downtown buildings seen in the film no longer exist due to major reconstruction following the strong earthquakes in October 1969. However, some, like the rough-stone Northwestern Pacific Railroad depot and the prominent Empire Building (built in 1910 with a gold-topped clock tower), still survive. A scene at the bank was filmed at the corner of Fourth Street and Mendocino Avenue (at present day Old Courthouse square); the Kress building on Fourth Street is also visible. However, the courthouse and bank are now gone. The Coen brothers' 2001 film The Man Who Wasn't There is set in Santa Rosa c. 1949.

Santa Rosa grew following World War II because it was the location for Naval Auxiliary Landing Field Santa Rosa, the remnants of which are now located in southwest Santa Rosa. The city was a convenient location for San Francisco travelers bound for the Russian River.

The population increased by two-thirds between 1950 and 1970, an average of 1,000 new residents a year over the 20-year period. Some of the increase was from immigration, and some from annexation of portions of the surrounding area.

In 1958 the United States Office of Civil and Defense Mobilization designated Santa Rosa as one of its eight regional headquarters, with jurisdiction over Region 7, which included American Samoa, Arizona, California, Guam, Hawaii, Nevada, and Utah. Santa Rosa continued as a major center for civil defense activity (under the Office of Emergency Planning and the Office of Emergency Preparedness) until 1979 when the Federal Emergency Management Agency (FEMA) was created in its place, ending the civil defense's 69-year history.

When the City Council adopted the city's first modern General Plan in 1991, the population was about 113,000. In the 21 years following 1970, Santa Rosa grew by about 3,000 residents a year—triple the average growth during the previous twenty years.

Santa Rosa 2010, the 1991 General Plan, called for a population of 175,000 in 2010. The Council expanded the city's urban boundary to include all the land then planned for future annexation, and declared it would be Santa Rosa's "ultimate" boundary. The rapid growth that was being criticized as urban sprawl became routine infill development.

At the first five-year update of the plan, in 1996, the Council extended the planning period by ten years, renaming it Vision 2020 (updated to Santa Rosa 2020, and then again to Santa Rosa 2030 Vision), and added more land and population. Now the City projects a population of 195,000 in 2020.

Santa Rosa annexed the community of Roseland in November 2017.

Beginning on the night of October 8, 2017, five percent of the city's homes were destroyed in the Tubbs Fire, a 45,000-acre wildfire that claimed the lives of at least 19 people in Sonoma County. Named after its origin near Tubbs Lane and Highway 128 in adjacent Napa County, the fire became a major section of the most destructive and third deadliest firestorm in California history. Most homes in the Coffey Park, Larkfield-Wikiup, and Fountain Grove neighborhoods were destroyed.

A notable exception to the destruction in the area was the protection of more than 1,000 animals at the renowned Safari West Wildlife Preserve northeast of Santa Rosa. All of the preserve's animals were saved by owner Peter Lang, who, at age 76, single-handedly fought back the flames for more than 10 hours using garden hoses.

The fire burned strongly for over seven days, bringing the largest aerial attack in history to Sonoma County skies.^{[citation needed]} Some of the airplanes include a massive Boeing 747 Supertanker, a C-130, S-2, OV-10, DC-10 Air Tanker UH-60 Blackhawk, and Boeing CH-47 Chinook helicopter.^{[citation needed]} Every police agency in the San Francisco Bay Area was called in to help.^{[citation needed]} Firefighting crews from across California and as far away as Australia came to aid in extinguishing the fire.^{[citation needed]} The fires, alongside the December 2017 Southern California wildfires, comprised the most destructive year of California wildfires on record.^{[citation needed]}

A graph of the population growth of Santa Rosa (to 2010).

The 2010 United States Census reported that Santa Rosa had a population of 167,815. The population density was 4,043.8 people per square mile (1,561.3/km²). The racial makeup of Santa Rosa was: 119,158 White (59.7% non-Hispanic white), 4,079 (2.4%) African American, 2,808 (1.7%) Native American, 8,746 (5.2%) Asian (1.0% Filipino, 1.0% Chinese, 0.8% Vietnamese, 0.6% Indian, 0.5% Cambodian, 0.5% Laotian, 0.3% Japanese, 0.3% Korean, 0.1% Thai, 0.1% Nepalese), 810 (0.5%) Pacific Islander (0.2% Fijian, 0.1% Samoan, 0.1% Hawaiian, 0.1% Guamanian), 23,723 (14.1%) from other races, 8,491 (5.1%) from two or more races. Hispanic or Latino of any race were 47,970 persons (28.6%). Among the Hispanic population, 98% of Santa Rosa is Mexican, 0.8% Salvadoran, and 0.4% Puerto Rican.

The Census reported that 164,405 people (98.0% of the population) lived in households, 1,697 (1.0%) lived in non-institutionalized group quarters, and 1,713 (1.0%) were institutionalized.

There were 63,590 households, out of which 20,633 (32.4%) had children under the age of 18 living in them, 27,953 (44.0%) were opposite-sex married couples living together, 7,663 (12.1%) had a female householder with no husband present, 3,615 (5.7%) had a male householder with no wife present. There were 5,020 (7.9%) unmarried opposite-sex partnerships, and 757 (1.2%) same-sex married couples or partnerships. 18,021 households (28.3%) were made up of individuals, and 7,474 (11.8%) had someone living alone who was 65 years of age or older. The average household size was 2.59. There were 39,231 families (61.7% of all households); the average family size was 3.18.

In terms of age cohorts, there were 39,217 people (23.4%) under the age of 18, 15,982 people (9.5%) aged 18 to 24, 46,605 people (27.8%) aged 25 to 44, 43,331 people (25.8%) aged 45 to 64, and 22,680 people (13.5%) who were 65 years of age or older. The median age was 36.7 years.^{[citation needed]} For every 100 females, there were 95.2 males. For every 100 females age 18 and over, there were 92.2 males.

There were 67,396 housing units at an average density of 1,624.0 per square mile (627.0/km²), of which 34,427 (54.1%) were owner-occupied, and 29,163 (45.9%) were occupied by renters. The homeowner vacancy rate was 2.0%; the rental vacancy rate was 5.0%. 87,244 people (52.0% of the population) lived in owner-occupied housing units and 77,161 people (46.0%) lived in rental housing units.

As of 2011, there are an estimated 4,539 homeless people living in Sonoma County, many of whom live in Santa Rosa.

Santa Rosa's Hispanic population, mainly of Mexican descent, while spread out through the city, is concentrated within the western part of Santa Rosa. The highest percentage of Hispanic residents in Santa Rosa is in the Apple Valley Lane/Papago Court neighborhood, at 87%.

The Southeast Asian communities, mainly Vietnamese, Laotian, and Cambodian, are concentrated within the western Santa Rosa neighborhoods of Bellevue Ranch, Roseland, and West Steele areas. The northeast neighborhoods of Skyhawk and Fountaingrove have the most populous Chinese communities.

As of the census of 2000, there were 63,153 households, of which 30.9% had children under the age of 18 living with them, 46.9% were married couples living together, 11.0% had a female householder with no husband present, and 37.3% were non-families. 27.8% of all households were made up of individuals, and 11.9% had someone living alone who was 65 years of age or older. The average household size was 2.57 and the average family size was 3.14.

In terms of age cohorts, 24.3% of the population was under the age of 18, 9.5% was from 18 to 24, 30.0% from 25 to 44, 22.3% from 45 to 64, and 13.9% were 65 years of age or older. The median age was 36 years. For every 100 females, there were 95.4 males. For every 100 females age 18 and over, there were 91.8 males.

The median income for a household in the city was $50,931, and the median income for a family was $59,659. Males had a median income of $40,420 versus $30,597 for females. The per capita income for the city was $24,495. 8.5% of the population and 5.1% of families were below the poverty line. Out of the total population, 9.5% of those under the age of 18 and 4.7% of those 65 and older were living below the poverty line.

Neighborhoods such as South Park in south Santa Rosa, and Roseland, West Ninth District, and Apple Valley in west Santa Rosa, are most vulnerable to criminal activity. Acts of crime in these neighborhoods are commonly burglaries, graffiti, and violent gang activity. Street gangs such as Sureños and Norteños have large concentrations throughout Santa Rosa. In 2011, there were 5 homicides, 58 rapes, 134 robberies, 485 aggravated assaults, and 637 burglaries. The violent crime rate for Santa Rosa (401.7 per 100,000 people) is slightly lower than the rate of California (411.1 per 100,000 people) and higher than that of the entire U.S. (386.3 per 100,000 people).

Santa Rosa saw the second-highest rate of couples in same-sex marriages among United States cities in 2018, behind only San Francisco.