The Ohlone tribe of Native Americans inhabited this area at least by 1500 to 1000 BC. One tumulus was discovered in 1951 during development of the University Village subdivision near today's Costaño School. After a year-long excavation of 60 graves and 3,000 artifacts, researchers concluded Native Americans had utilized the area as a cemetery and camp, rather than as a permanent settlement. In later years another mound was found near Willow Road and the railroad right-of-way.From the 1850s through the 1940s, the area which was to become East Palo Alto went through many changes. In 1849, Isaiah Churchill Woods (1825–1880) attempted to make the area around what is now Cooley Landing in the northeast of the current city a major shipping town and named the area Ravenswood. In 1868, after Woods' investments failed he sold the wharf to Lester Phillip Cooley (1837–1882), who leased the land to the brick factory Hunter and Schakleford. When the brick factory left the landing in 1884, the land around the landing was reverted to a ranch.With the outbreak of World War I, the north side of East Palo Alto became a military training ground, of which only the Veterans Administration Hospital in Menlo Park still exists (now as part of the VA Sierra Pacific Network). In the 1940s, East Palo Alto was a farming community with many Japanese residents. During the war, the Japanese were forced out, many to relocation centers, and did not return after the war. In the 1950s the farms were built over with cheap housing and many African-American families moved in. The current demographics of East Palo Alto are largely a result of redlining housing policies and events that occurred in the 1950s. In particular, in 1954 the then-president of the California Real Estate Association, Floyd Lowe, implemented a strategy that turned a neighborhood on the East side of Palo Alto from predominantly white to predominantly black in a very short amount of time. He did this by "blockbusting," which is a strategy that was employed all over the country to similar results. Blockbusting involves instilling panic in white neighborhoods by warning of a "Negro invasion" when a black family considers purchasing a house in an area, in order to produce white flight and an ensuing drop in property values, which can then be purchased at a heavy discount and sold or rented to African Americans for a profit. In 1954, Lowe alerted the neighborhood that a "Negro invasion" was imminent, and as intended, white flight ensued. Lowe profited due to the low prices at which the white families fleeing were willing to sell their homes, and within a few years, the demographics of the area had flipped. As white-owned businesses fled the area, it became poorer and overcrowded – a legacy that has persisted. This segregationist act was never questioned by the government, and it led to many of the demographic and socioeconomic differences that exist between Palo Alto and East Palo Alto today.These differences in demographics and wealth perversely accelerated with the introduction of the Community Reinvestment Act of 1977, which banned redlining. Home prices doubled by 1979, and many of the more educated and upwardly mobile African Americans took advantage of their newfound freedom to move into wealthier communities with more amenities, leaving the remaining community even poorer and with less access to home ownership than had been the case before the Act. During the civil rights movement of the 1960s there was a renewed interest in African history, one expression of which was a fad for Swahili. In 1968 the area was almost renamed Nairobi, after the center of the Swahili-speaking area, to reflect the population's African roots. Critics of the change pointed out that Nairobi was the capital of Kenya, in East Africa, and had little to do with the cultural roots of most black Americans. In the end, the change was not made. Historically East Palo Alto had relatively little shopping and business compared to surrounding areas, and most of it constituted an unincorporated "island" within San Mateo County, depending on county government for services and on the San Mateo County Sheriff for police protection and ineligible for many revenue benefits requiring city status. After several years of pro-incorporation campaigning by local community groups, a 1982 ballot measure that was stopped by a lawsuit, and a subsequent election the next year, East Palo Alto became a city on July 1, 1983, with Barbara A. Mouton as its first Mayor. However, because of subsequent legal challenges to the last ballot measure, it was not until 1987 that the city was officially recognized as such. The legal challenges were led by former U.S. Congress member Pete McCloskey, who represented one of the real-estate brokers whose original blockbusting campaign had turned EPA into a mostly black town. The final tally was 1,777 for and 1,764 against, a margin of 13 votes and a majority of 50.2%.Significant gentrification occurred in East Palo Alto from around the founding of Facebook, with the construction of a large shopping center named Ravenswood 101—including a Home Depot, a Best Buy, and an IKEA store—and several upscale housing communities intended for high-earning Silicon Valley workers. This development faced opposition from some residents, who charged that it priced locals out of one of the region's only affordable communities while providing only low-paying retail jobs and consuming disproportionate land area (2.2 square miles). Supporters pointed to an increased tax base. In 2008, after twenty years without a supermarket, East Palo Alto individuals and organizations established the East Palo Alto Community Farmers' Market. In November 2009, the Mi Pueblo Food Center grocery store opened in the Ravenswood 101 shopping center in the location of the former Circuit City store. Mi Pueblo was the city's first full-service supermarket in 23 years.Starting in 2006, a large real estate investor, Page Mill Properties, purchased almost the entire west side of East Palo Alto and contested most of the city's rent control laws in what some claimed was a 'predatory equity scheme'. Page Mill left East Palo Alto in the fall of 2009 after defaulting on a $240-million bank loan.

East Palo Alto is located in San Mateo County. Despite its name, it lies almost entirely north, and not east of Palo Alto. It is bordered on the west by Menlo Park, to the south by Palo Alto, and to the east by the San Francisco Bay. The San Francisquito Creek defines its southern edge. To the north are Ravenswood Point and the western end of the Dumbarton Bridge in Menlo Park. According to the United States Census Bureau, the city has a total area of 2.6 square miles (6.7 km2), of which 2.5 square miles (6.5 km2) is land and 0.1 square miles (0.26 km2) of it (4.11%) is water.

The 2010 United States Census reported that East Palo Alto had a population of 28,155. The population density was 10,777.1 inhabitants per square mile (4,161.1/km2). The racial makeup of East Palo Alto was 1,754 (6.2%) White, 4,704 (16.7%) African American, 120 (0.4%) Native American, 1,057 (3.8%) Asian, 2,118 (7.5%) Pacific Islander, 10,694 (38.0%) from other races, and 1,358 (4.8%) from two or more races. Hispanic or Latino of any race were 18,147 persons (64.5%). Among the Hispanic population, 15,319 (54.4%) are Mexican, 69 (0.2%) are Puerto Rican, 23 (0.1%) are Cuban, and 2,736 (9.7%) are other Hispanic or Latino. The Census reported that 28,001 people (99.5% of the population) lived in households, 150 (0.5%) lived in non-institutionalized group quarters, and 4 (0%) were institutionalized. There were 6,940 households, out of which 3,767 (54.3%) had children under the age of 18 living in them, 3,144 (45.3%) were opposite-sex married couples living together, 1,510 (21.8%) had a female householder with no husband present, 625 (9.0%) had a male householder with no wife present. There were 529 (7.6%) unmarried opposite-sex partnerships, and 59 (0.9%) same-sex married couples or partnerships. 1,196 households (17.2%) were made up of individuals, and 316 (4.6%) had someone living alone who was 65 years of age or older. The average household size was 4.03. There were 5,279 families (76.1% of all households); the average family size was 4.38. The population was spread out, with 8,976 people (31.9%) under the age of 18, 3,487 people (12.4%) aged 18 to 24, 8,897 people (31.6%) aged 25 to 44, 5,120 people (18.2%) aged 45 to 64, and 1,675 people (5.9%) who were 65 years of age or older. The median age was 28.1 years. For every 100 females, there were 102.7 males. For every 100 females age 18 and over, there were 102.5 males. There were 7,819 housing units at an average density of 2,992.9/sq mi (1,155.6/km2), of which 2,971 (42.8%) were owner-occupied, and 3,969 (57.2%) were occupied by renters. The homeowner vacancy rate was 2.1%; the rental vacancy rate was 13.3%. 12,628 people (44.9% of the population) lived in owner-occupied housing units and 15,373 people (54.6%) lived in rental housing units.

As of the census of 2000, there were 35,791 people, 7,104 households, and 5,793 families residing in the city. The population density was 14,327.6 inhabitants per square mile (5,531.9/km2). There were 8,046 housing units at an average density of 4,444.4/sq mi (1,716.0/km2). 21.3% spoke English, 64.8% Spanish, 9.5% Pacific Island languages, 0.4% Chinese or Mandarin, other Indo-European 1.4%, and other language 1.3%, as their first language from estimate census 2009. There were 7,104 households, of which 41.7% had children under the age of 18 living with them, 44.4% were married couples living together, 19.5% had a female householder with no husband present, and 28.5% were non-families. 22.2% of all households were made up of individuals, and 5.1% had someone living alone who was 65 years of age or older. The average household size was 6.24 and the average family size was 7.65. In the city, the population was spread out, with 47.1% under the age of 18, 19.5% from 18 to 24, 31.2% from 25 to 44, 11.1% from 45 to 64, and 3.6% who were 65 years of age or older. The median age was 21 years. For every 100 females, there were 109.2 males. For every 100 females age 18 and over, there were 108.9 males. The median income for a household in the city was $44,006, and the median income for a family was $42,342. Males had a median income of $25,631 versus $28,044 for females. The per capita income for the city was $13,774. About 22.2% of families and 21.0% of the population were below the poverty line, including 20.1% of those under age 18 and 14.7% of those age 65 or over.

U.S. Route 101 cuts through the southern part of the city, with two on ramps and off ramps in the city (University and Willow). There are frontage roads on either side of the freeway. The Dumbarton Bridge in neighboring Menlo Park connects East Palo Alto to Alameda County, which lies to the east across San Francisco Bay, and carries State Route 84 into East Palo Alto toward U.S. 101. Public transportation is provided by SamTrans.

The Ravenswood City School District has its headquarters in East Palo Alto.The schools in the city are Costaño School of the Arts, Belle Haven Elementary, Los Robles-Ronald McNair Academy, and Cesar Chavez Ravenswood Middle School.The Sequoia Union High School District operates the zoned high schools in the area. Between 1958 and 1976 East Palo Alto had its own high school, Ravenswood High School. After the school was closed because of low enrollment, the building was demolished in 1995 to make room for the Gateway 101 Shopping Center. Following the closure of Ravenswood High School, East Palo Alto's high school students were bused out of the city to other schools in the region, primarily Carlmont High School in Belmont. Some have called for re-opening Ravenswood High School in a new location in East Palo Alto.In 2014, the Sequoia Union High School District discontinued the practice of busing. Today, East Palo Alto residents are zoned to Menlo-Atherton High School in Atherton. Through the district Open Enrollment process, some residents choose to attend Carlmont, Woodside High School in Woodside, or Sequoia High School in Redwood City. Alternatively, East Palo Alto Academy (opened in 2001 as East Palo Alto High School) and East Palo Alto Phoenix Academy (opened 2006) are charter high schools in East Palo Alto. There is also a private high school, Eastside College Preparatory, which opened in 1996.Every year, parents of incoming minority children in kindergarten through grade 2 can enter a lottery (if there are more requests than the 135 slots available) to send their children to neighboring school districts under the Tinsley Voluntary Transfer Program.

San Mateo County Libraries operates the East Palo Alto Library, located in the municipal building at 2415 University Avenue.

According to the city's 2021 Annual Comprehensive Financial Report, the city's top employers were: The total city employment for the year ended June 30, 2021 was 14,500, and the total city employment for 2014 was 13,800.

The local area around the Dumbarton Bridge is an important ecological area, hosting many species of birds, fish and mammals. The California clapper rail is known to be present in the western bridge terminus area. The bridge is not a significant source of noise affecting East Palo Alto; however, it does cause significant traffic backups at rush hour and the city is also affected by noise from events at the nearby Shoreline Amphitheatre in Mountain View. The Baylands Nature Preserve borders the city of East Palo Alto. The long trail along the marshland connects Mountain View, Palo Alto, and East Palo and it is used by bike commuters every day.