Simi Valley was once inhabited by the Chumash people, who also settled much of the region from the Salinas Valley to the Santa Monica Mountains, with their presence dating back 10,000–12,000 years. Around 5,000 years ago these tribes began processing acorns, and harvesting local marshland plants. Roughly 2,000 years later, as hunting and fishing techniques improved, the population increased significantly. Shortly after this sharp increase a precious stone money system arose, increasing the viability of the region by offsetting fluctuations in available resources relating to climate changes. The native people who inhabited Simi Valley spoke an interior dialect of the Chumash language, called Ventureño.

Simi Valley's name derived from the Chumash word Shimiyi, which refers to the stringy, thread-like clouds that typify the region. The name could have derived from strands of mist from coastal fog that move into the Oxnard Plain and wind their way up the Calleguas Creek and the Arroyo Las Posas into Simi Valley. The origin of the name was preserved because of the work of the anthropologist John P. Harrington, whose brother, Robert E. Harrington lived in Simi Valley. Robert Harrington later explained the name: "The word Simiji in Indian meant the little white wind clouds so often seen when the wind blows up here and Indians living on the coast, would never venture up here when those wind clouds were in the sky. The word Simiji was constructed by whites to the word Simi. There are other explanations about the name Simi, but this one was given to me by my brother who worked over 40 years for the Smithsonian Institution and it seems most plausible to me".

Three Chumash settlements existed in Simi Valley during the Mission period in the late 18th and early 19th century: Shimiyi, Ta’apu (present-day Tapo Canyon), and Kimishax or Quimisac (Happy Camp Canyon west of Moorpark College). There are many Chumash cave paintings in the area containing pictographs, including the Burro Flats Painted Cave in the Burro Flats area of the Simi Hills, located between the Simi Valley, and West Hills and Bell Canyon. The cave is located on private land owned by Boeing, formerly operated by Rocketdyne for testing rocket engines and nuclear research. Other areas containing Chumash Native American pictographs in the Simi Hills are for instance by Lake Manor and Chatsworth.

The first Europeans to visit Simí Valley were members of the Spanish Portolá expedition (1769–1770), the first European land entry and exploration of the present-day state of California. The expedition traversed the valley on January 13–14, 1770, traveling from Conejo Valley to San Fernando Valley. They camped near a native village in the valley on the 14th.

Rancho Simí, also known as Rancho San José de Nuestra Señora de Altagracia y Simí, was a 113,009-acre (457 km²) Spanish land grant in eastern Ventura and western Los Angeles counties granted in 1795 to Santiago Pico. After Santiago Pico's death in 1815, the Rancho was regranted to Santiago's sons Javier Pico and his two brothers, Patricio Pico and Miguel Pico, members of the prominent Pico family of California.Rancho Simí was the earliest Spanish colonial land grant within Ventura and Santa Barbara Counties. The name derives from Shimiji, the name of the Chumash Native American village here before the Spanish. It was the largest Spanish or Mexican land grant given in Ventura County, and one of the largest given in California^{[circular reference]}. The Simi Adobe-Strathearn House, later the home of Robert P. Strathearn and family, served as the headquarters of the rancho.

José de la Guerra y Noriega, a Captain of the Santa Barbara Presidio, who had begun to acquire large amounts of land in California to raise cattle, purchased Rancho Simí from the Pico family in 1842. After Jose de la Guerra's death in 1858, the sons of Jose de la Guerra continued to operate the ranchos. The end of their prosperity came when several years of drought in the 1860s caused heavy losses. In 1865, the De la Guerras lost the ownership of El Rancho Simí excluding the Rancho Tapo. El Rancho Tapo was part of the original 113,009-acre Rancho Simí grant, but sometime around 1820–1830, the Rancho Tapo came to be thought of as a separate place within Rancho Simí. The last of the De la Guerras to live in Simí Valley retreated to a 14,400-acre portion of the original rancho that was known as the Tapo Rancho. As late as February 1877, Juan De la Guerra was reported in county newspapers to be preparing to plant walnuts in the Tapo, which appears to be the final mention of their farming in relation to the original Simí grant.

The De la Guerra heirs tried every legal means, but by the 1880s, the Rancho Tapo also slipped from their ownership, as had the rest of the Rancho.

The Pioneer, or ‘American,’ period in Simi Valley began with the 96,000-acre purchase of El Rancho Simí by an eastern speculator named Thomas A. Scott (1814–1882), who had made his money as an investor in the Pennsylvania Railroad during the Civil War. He was president of the Pennsylvania Railroad, and a partner in Philadelphia and California Petroleum Company. Scouts came to California to purchase lands, and thus Scott acquired El Rancho Simí (1865). His goal was to locate sites for oil, since the first oil well had been developed in Titusville, Pennsylvania just a few years earlier (1859). Within a short time, a 27 year old young man named Thomas Bard was sent west by Scott to manage the California properties. In the late 1880s, Simí Land and Water Company was formed to see to the selling of the huge rancho in ranch-size properties. Some American farmers had begun to lease land in the greater Rancho Simí for farming.

The earliest Anglo American ranchers showed up in Simí Valley in the late 1860s into the 1870s. Charles Emerson Hoar was given the title of "first American farmer" by early Simí historian Janet Scott Cameron. He had purchased the Hummingbird's Nest Ranch in the northeast corner of the Valley, and he leased land from the new owners of the Simí Rancho for raising sheep, already a proven way of making a living.

Much of the Simí Rancho land continued, as in Spanish days, to be used for raising sheep, cattle and grain. Wheat prospered longer here than in the rest of the county because it was free of a disease called "rust." Barley soon became the really successful grain crop.

Agriculture and ranching dominated the landscape through the 1950s. Citrus, walnuts and apricots were all grown in Simi Valley. In the early 1960s modern residential development began to take place.

When Simí was an agricultural community, there were ranch houses that dotted the Valley. Four distinct communities also were located in the Valley (see 'Four Communities of Simi Valley' section below) prior to modern residential development. Though 1957 and 1958 brought the first ‘tract’ housing developments when the Dennis and Ayhens, Wright Ranch and Valley Vista tracts were built, the tremendous ‘boom’ in residential development took place beginning in 1960. The population which was 4,073 in 1950 doubled to 8,110 in 1960. By 1970 the population in Simi is reported by the census as 59,832.

The pioneers arrived in the late 1860s – 1870s and ever since, this has been ‘The Valley of Simi.’ But, not all the communities in the valley were known as ‘Simi.’ There was the township of Simi (known as ‘Simiopolis’ for about a six-month period in 1888, but then the name reverted to Simi). In the valley there were also the communities of Santa Susana, Community Center and the Susana Knolls (known first as Mortimer Park) at different points in time.

Simi – In the late 1887–1888, the incorporation of Simi Land and Water Company came about. El Rancho Simí was divided into ranches and farms by that corporation, and advertised for sale to midwestern and New England states. An investor group, the California Mutual Benefit Colony of Chicago, purchased land and laid out a townsite (located between First and Fifth Streets and from Los Angeles south to Ventura Ave), named it ‘Simiopolis’ and shipped twelve pre-cut, partially assembled houses from a lumberyard in Chicago via rail to Saticoy, then brought by wagon to Simi. These are known as ‘colony houses.’ This was the first ‘neighborhood’ in Simi. Stores sprung up on Los Angeles Ave, and the first Simi School was built in 1890 on Third and California Streets, and was used until Simi Elementary was built in the mid 1920s.

Santa Susana – In 1903 the Santa Susana Train Depot was built, and the railroad was complete through Simi Valley, except for the tunnel, which was completed in 1904. A small business community grew up near the Santa Susana Train Depot, which was located on the north side of Los Angeles Ave, just east of Tapo Street. Over time residential developments followed and the town of Santa Susana was born. The Depot was moved in 1975 by Rancho Simi Recreation and Park District to its current location off of Kuehner.

Community Center – In 1922 L.F. Roussey laid out the small development which became known as Community Center. The driving force behind this development was the need for a High School in Simi Valley, as well as an elementary school in a more central location in the valley. The FIRST graduating class from the very first Simi High School was 1924, Simi Elementary was completed in 1926, The Methodist Church (which is now the Cultural Arts Center) was built in 1924. Numerous houses were built in Community Center in the 1920s and 1930s. The Simi Valley Woman's Club was located there as well (the building which served as the clubhouse for the Woman's Club was moved from the town of Simi). The Woman's Club club house was used by many individuals and organizations as a community meeting place. It truly was a ‘community center.’

Mortimer Park (the Susana knolls) – The area that is now the Knolls was a nearly 1,800-acre parcel of land that was purchased by Mr. and Mrs. Lewis T. Mortimer in the early 1920s. They planned on selling the lots for cabins, or vacation homes. The lots, however, were very small (30 x 50 feet), and the Mortimers did not take the mountainous nature of the land into account, so quite often the lots were not buildable. Oftentimes several lots were needed to build structures. In 1944 the Garden Club, an active community organization in the area petitioned the county supervisors to change the name of Mortimer Park to the Susana Knolls.

The first attempt to incorporate the towns of Simi, the area known as Community Center (93065) and Santa Susana (93063) in 1966 was unsuccessful. The second attempt in 1969 was successful, with residents voting 6,454 to 3,685 in favor of incorporation. 59% of eligible voters turned out for this vote. Susana Knolls is an unincorporated area of the Valley. Voters also voted whether to call this newly incorporated city ‘Santa Susana’ or ‘Simi Valley.’ The name Simi Valley garnered 2,000 more votes than Santa Susana.

The 2,848 acres (1,153 ha) Santa Susana Field Laboratory located in the Simi Hills, was used for the development of pioneering nuclear reactors and rocket engines beginning in 1948. The site was operated by Atomics International and Rocketdyne (originally both divisions of the North American Aviation company). The Rocketdyne division developed a variety of liquid rocket engines. Rocket engine tests were frequently heard in Simi Valley. The Atomics International division of North American Aviation designed, built and operated the Sodium Reactor Experiment, the first United States nuclear reactor to supply electricity to a public power system.[Also from Wikipedia: The Boiling Water Reactors (BORAX) experiments were five reactors built between 1953 and 1964 by Argonne National Laboratory. They proved that the boiling water concept was a feasible design for an electricity-producing nuclear reactor. One of the BORAX reactors (III) was also the first in the world to power a city (Arco, Idaho) on July 17, 1955. Both claims can not be correct. ] The last nuclear reactor operated at SSFL in 1980 and the last rocket engine was produced in 2006. The SSFL has been closed to development and testing. The site is undergoing investigation and removal of the nuclear facilities and cleanup of the soil and groundwater. The Boeing Company, the US DOE, and NASA are responsible for the cleanup.

In July 1959, the Sodium Reactor Experiment suffered a serious incident when 13 of the reactor's 43 fuel elements partially melted resulting in the controlled release of radioactive gas to the atmosphere. The reactor was repaired and returned to operation in September, 1960. The incident at the Sodium Reactor Experiment has been a source of controversy in the community. Technical analysis of the incident intended to support a lawsuit against the current landowner (The Boeing Company) asserts the incident caused the much greater release of radioactivity than the accident at Three Mile Island. Boeing's technical response concludes the monitoring conducted at the time of the incident, shows only the allowable amount of radioactive gasses were released, and a Three Mile Island-scale release was not possible. The case was settled, it is reported, with a large payment by Boeing. In September 2009, The U.S. Department of Energy sponsored a public workshop where three nuclear reactor experts shared their independent analysis of the July, 1959 incident.

The Santa Susana Field Laboratory also hosted the Energy Technology Engineering Center. The center performed the design, development and testing of liquid metal reactor components for the United States Department of Energy from 1965 until 1998.

The Santa Susana Field Laboratory includes sites identified as historic by the American Institute of Aeronautics and Astronautics and by the American Nuclear Society. The National Register of Historic Places listed Burro Flats Painted Cave is located within the Santa Susana Field Laboratory, on a portion of the site owned by the U.S. Government. The drawings within the cave have been termed "the best preserved Indian pictograph in Southern California."

Four officers of the Los Angeles Police Department (Stacey Koon, Laurence Powell, Timothy Wind, and Theodore Briseno) were accused of using unnecessary force in a March 3, 1991 beating of an African-American motorist Rodney Glen King. The case known as the Rodney King Trials was based on footage recorded on home video by a bystander (George Holliday). The now-infamous video was broadcast nationally and globally and caused tremendous response because the beating was believed to be racially motivated. Due to the heavy media coverage of the arrest, Judge Stanley Weisberg of the California Court of Appeals approved a change of venue to neighboring Ventura County, using an available courtroom in Simi Valley for the state case against the officers.

On April 29, 1992, a Ventura County jury acquitted three of the four officers (Koon, Wind, and Briseno) and did not reach a verdict on one (Powell). Many believed that the unexpected outcome was a result of the racial and social make-up of the jury, which included ten white people, one Filipino person, and one Hispanic woman. None were Simi Valley residents. Among the jury were three who had been security guards or in military service. The acquittal led to the 1992 Los Angeles riots and mass protest around the country.

In 1972, Boys Town West was founded in the eastern end of Simi Valley. The youth camp/home facility is based on an older larger one in Boys Town, Nebraska.

The 2010 United States Census reported that Simi Valley had a population of 124,237. The population density was 2,940.8 people per square mile (1,135.4/km²). The racial makeup of Simi Valley was 93,597 (75.3%) White, 1,739 (1.4%) African American, 761 (0.6%) Native American, 11,555 (9.3%) Asian, 178 (0.1%) Pacific Islander, 10,685 (8.6%) from other races, and 5,722 (4.6%) from two or more races. Hispanic or Latino of any race were 10,938 persons (23.3%); 16.2% of Simi Valley's population were Mexican-American, 1.2% Salvadoran, 0.9% Guatemalan, 0.6% Puerto Rican, 0.6% Peruvian, 0.3% Cuban, 0.3% Argentine, 0.2% Honduran, 0.2% Nicaraguan, and 0.2% Ecuadorian. Among Asian-Americans, 2.7% of Simi Valley's population were Indian-Americans, 2.2% Filipino, 1.2% Chinese, 1.0% Vietnamese, 0.7% Korean, 0.5% Japanese, 0.2% Thai, 0.1% Pakistani. The majority of Simi Valley's population was made up of Caucasian-Americans; the largest groups of whites were 16.7% German-American, 11.3% English, 8.5% Italian, 3.4% French, 3.1% Polish, 2.3% Norwegian, 2.3% Swedish, 2.1% Scottish and 2% Dutch.

The Census reported that 123,577 people (99.5% of the population) lived in households, 482 (0.4%) lived in non-institutionalized group quarters, and 178 (0.1%) were institutionalized. There were 41,237 households, out of which 16,765 (40.7%) had children under the age of 18 living in them, 24,824 (60.2%) were opposite-sex married couples living together, 4,659 (11.3%) had a female householder with no husband present, 2,214 (5.4%) had a male householder with no wife present. There were 1,975 (4.8%) unmarried opposite-sex partnerships, and 291 (0.7%) same-sex married couples or partnerships. 7,087 households (17.2%) were made up of individuals, and 3,013 (7.3%) had someone living alone who was 65 years of age or older. The average household size was 3.00. There were 31,697 families (76.9% of all households); the average family size was 3.33.

The population was spread out, with 31,036 people (25.0%) under the age of 18, 11,088 people (8.9%) aged 18 to 24, 33,890 people (27.3%) aged 25 to 44, 35,046 people (28.2%) aged 45 to 64, and 13,177 people (10.6%) who were 65 years of age or older. The median age was 37.8 years. For every 100 females, there were 96.6 males. For every 100 females age 18 and over, there were 94.4 males. There were 42,506 housing units at an average density of 1,006.1 per square mile (388.5/km²), of which 30,560 (74.1%) were owner-occupied, and 10,677 (25.9%) were occupied by renters. The homeowner vacancy rate was 1.2%; the rental vacancy rate was 4.6%. 93,181 people (75.0% of the population) lived in owner-occupied housing units and 30,396 people (24.5%) lived in rental housing units.

As of the census of 2000, there were 111,351 people, 36,421 households, and 28,954 families residing in the city. The population density was 1,097.3/km² (2,841.9/mi²). There were 37,272 housing units at an average density of 367.3/km² (951.3/mi²). The racial makeup of the city was 81.33% White, 1.26% Black or African American, 0.70% Native American, 6.33% Asian, 0.14% Pacific Islander, 6.50% from other races, and 3.74% from two or more races. 16.82% of the population were Hispanic or Latino of any race.

There were 36,421 households, out of which 42.5% had children under the age of 18 living with them, 63.9% were married couples living together, 10.7% had a female householder with no husband present, and 20.5% were non-families. 14.7% of all households were made up of individuals, and 4.9% had someone living alone who was 65 years of age or older. The average household size was 3.04 and the average family size was 3.33.

In the city, the population was spread out, with 28.4% under the age of 18, 7.9% from 18 to 24, 32.9% from 25 to 44, 23.1% from 45 to 64, and 7.6% who were 65 years of age or older. The median age was 35 years. For every 100 females, there were 97.9 males. For every 100 females age 18 and over, there were 95.6 males.

According to a 2007 estimate, the median income for a household in the city was $88,406, and the median income for a family was $91,658. 10.2% of the population and 7.4% of families were below the poverty line. In 2016, the median income for a household in Simi Valley has increased to $90,210 according to the U.S. Census Bureau. The median per capita income for the past 12 months (2015) was $37,459. Sales tax was at 7.25% and income taxes were at 8.00%. The current unemployment rate was at 4.80% with a 0.36% recent job growth compared to the National Unemployment Rate of 5.20% and a 1.59% job growth. The median cost of homes in Simi Valley was $450,500 with mortgages at a median of $2,456.