The first people of the Tualatin Valley were the Atfalati or Tualaty tribe of the Kalapuya, who inhabited the region for up to 10,000 years before white settlers arrived. The valley consisted of open grassland maintained through annual burning by the Atfalati, with scattered groves of trees along the streams. The Kalapuya moved from place to place in good weather to fish and hunt and to gather nuts, seeds, roots, and berries. Important foods included camas and wapato, and the Atfalati traded for salmon from Chinookan tribes near Willamette Falls on the Willamette River. During the winter, they lived in longhouses in settled villages, some near what became Hillsboro and Beaverton. Their population was greatly reduced after contact in the late 18th century with Europeans, who carried smallpox, syphilis, and malaria. Of the original population of 1,000 to 2,000 Atfalati reported in 1780, only 65 remained in 1851. In 1855, the U.S. government sent the survivors to the Grande Ronde reservation further west.

The European-American community was founded by David Hill, Isaiah Kelsey, and Richard Williams, who arrived in the Tualatin Valley in 1841, followed by six more pioneers in 1842. The locality went by two other names—East Tualatin Plains and Columbia—before it was named "Hillsborough" in February 1850 in honor of Hill, when he sold part of his land claim to the county. On February 5, 1850, commissioners chosen by the territorial legislature selected the community to be the seat of the county government. Hill was to be paid $200 for his land after plots had been sold for the town site, but he died before this occurred, and his widow Lucinda received the funds. The town's name was later simplified to Hillsboro. A log cabin was built in 1853 to serve as the community's first school, which opened in October 1854. Riverboats provided transportation to Hillsboro as early as 1867 when the side-wheel steamer Yamhill worked on the Tualatin River.

In 1871, the Oregon and California Railroad line was extended to the area, but it ran just south of town because the city did not want to give the railroad land in exchange for the rail connection. Hillsboro was incorporated as the Town of Hillsboro on October 19, 1876, by the Oregon Legislature. The first mayor was A. Luelling, who took office on December 8, 1876, and served a one-year term. Notable later mayors included Congressman Thomas H. Tongue (1882 and 1886) and state senator William D. Hare (1885). In 1923, the city altered its charter and adopted a council-manager government with a six-person city council, a part-time mayor who determined major policies, and a city manager who ran day-to-day operations.

On September 30, 1908, 5,000 people gathered as the Oregon Electric Railway opened a connection between the city and Portland with an interurban electric rail line, the first to reach the community. In January 1914, the Southern Pacific Railroad introduced its own interurban service, known as the Red Electric, on a separate line and serving different communities between Hillsboro and Portland. SP discontinued its Hillsboro service on July 28, 1929, while the Oregon Electric Railway's passenger service to Hillsboro lasted until July 1932.

A brick building was constructed in 1852 to house the county government, followed by a brick courthouse in 1873. In 1891, the courthouse was remodeled and a clock tower was added, and the building was expanded with an annex in 1912. A new courthouse replaced the brick structure in 1928. The last major remodel of the 1928 structure occurred in 1972, when the Justice Services Building was built and incorporated into the existing building.

The city's first fire department was a hook and ladder company organized in 1880 by the board of trustees (now city council). A drinking water and electricity distribution system added in 1892–93 gave the town three fire hydrants and minimal street lighting. Hillsboro built its first sewer system in 1911, but sewage treatment was not added until 1936. In 1913, the city built its own water system, and the first library, Carnegie City Library, opened in December 1914. From 1921 to 1952, the world's second-tallest radio tower stood on the south side of the city, but in 1952, the wireless telegraph tower was demolished. During the 1950s and 1960s, the privately owned company Tualatin Valley Buses, Inc., provided transit service connecting Hillsboro with Beaverton and Portland. It was taken over by the publicly owned transit agency TriMet in 1970.

In 1972, the Hillsboro City Council passed a Green River Ordinance banning door-to-door solicitation, but it was ruled unconstitutional by the Oregon Supreme Court in a 1988 decision. The court determined that the city ordinance was overly broad, in a case that was seen as a test case for many similar laws in the state. In 1979, Intel opened its first facility in Hillsboro. The Hawthorn Farm campus was followed by the Jones Farm campus adjacent to the airport in 1982, and finally by the Ronler Acres campus in 1994. TriMet opened a Metropolitan Area Express (MAX) light rail line into the city in 1998. A cultural center was added in 2004, and a new city hall was completed in 2005. In 2008, SolarWorld opened a facility producing solar wafers, crystals, and cells, the largest plant of its kind in the Western Hemisphere. U.S. President Barack Obama visited the city and Intel's Ronler Acres campus in February 2011.

Properties listed on the National Register of Historic Places (NRHP) in and around Hillsboro include the Old Scotch Church, completed in 1876 north of the city. Near the Orenco neighborhood is Imbrie Farm, which includes a house built in 1866 and the Frank Imbrie Barn, both of which McMenamins converted for use as a brewpub. Built in 1935, the Harold Wass Ray House is near Intel's Hawthorn Farm campus.Historic properties in downtown include the Zula Linklater House (completed 1923), Rice–Gates House (1890), Edward Schulmerich House (c. 1915), and Charles Shorey House (c. 1908). The Richard and Helen Rice House is adjacent to the Sunset Highway on the north side of the city and houses the Rice Northwest Museum of Rocks and Minerals. The Old Washington County Jail had been at the Washington County Fairgrounds in the city, but was restored and moved to the Washington County Museum outside the city in 2004, and was de-listed from the NRHP in 2008. In 2007, the Manning–Kamna Farm was added to the NRHP and includes 10 buildings, dating to as early as 1883. The Malcolm McDonald House in Orenco was added to the Registry in 2015.

Hillsboro's population grew from 402 in 1880 to 2,016 by 1910, making it the county's most populated city, according to the 1910 census data. By 1970, it had increased to more than 15,000, although neighboring Beaverton had overtaken it as the county's most populous city. By 1990 there were more than 37,000 residents, and commuters raised this to 110,000 during daytime. At the 2010 Census, the population was 91,611, fifth in rank among the state's largest cities behind Portland, Eugene, Salem and Gresham and slightly ahead of Beaverton, which ranked sixth. This figure was a 30.5 percent increase from Hillsboro's 70,186 residents in 2000, which made Hillsboro the fourth fastest-growing city in the state during the 2000s (decade), and the fastest-growing city in the Willamette Valley over the same period. In 2007, there were 17,126 houses lived in by their owners, with an average home price in the city of $246,900.Bloomberg Businessweek listed the city as the fastest-growing in Oregon for the period between 1990 and 2010, for cities with populations over 10,000.

As of the census of 2010, there were 91,611 people, 33,289 households, and 22,440 families residing in the city. The population density was about 3,800 inhabitants per square mile (1,500/km²). There were 35,487 housing units at an average density of about 1,500 per square mile (600/km²). The racial makeup of the city was approximately 73% White, 2% African American, 1% Native American, 9% Asian, less than 1% Pacific Islander, 10% from other races, and 5% from two or more races. Hispanic or Latino of any race were about 23% of the population.

There were 33,289 households, of which about 38% had children under the age of 18 living with them, 51% were married couples living together, 11% had a female householder with no husband present, 5% had a male householder with no wife present, and 33% were non-families. About 24% of all households were made up of individuals, and 6% had someone living alone who was 65 years of age or older. The average household size was 2.71 and the average family size was 3.24.

The median age in the city was 32 years. About 27% of residents were under the age of 18; 9% were between the ages of 18 and 24; 35% were from 25 to 44; 21% were from 45 to 64; and 8% were 65 years of age or older. The gender makeup of the city was 50.2% male and 49.8% female.

At the time of the 2000 census, there were 25,079 households, of which about 38% had children under the age of 18 living with them, 55% were married couples living together, 9% had a female householder with no husband present, and 32% were non-families. About 23% of all households were made up of individuals, and 5% had someone living alone who was 65 years of age or older. The average household size was 2.8 and the average family size was 3.3.

City residents included about 28% under the age of 18, 11% from 18 to 24, 37% from 25 to 44, 17% from 45 to 64, and 6% who were 65 years of age or older. The median age was 30 years. For every 100 females, there were about 106 males.

The median household income was about $52,000 and the median family income was $57,000. Males had a median income of $41,000 compared to $30,000 for females. The per capita income for the city was about $22,000. Approximately 6% of families and 9% of the population were below the poverty line, including 11% of those under age 18 and 8% of those age 65 or over. In 2007, 28% of people 25 and older held at least a bachelor's degree, while an additional 11% held an associate degree. Those with less than a high school diploma made up 15% of the population, and 22% of residents had more than a high school diploma but less than a college degree.

For the year 2011, the city had 180 violent crimes reported to law enforcement, and 2,154 reports of property crimes. The violent crime rate was 157.2 per 100,000 people compared to a national average of 309.3 and 287 for Oregon. Property crime nationally was 3,335 per 100,000 compared to 3,203 in Hillsboro, and 4,402 for the state. Violent offenses include forcible rape, robbery, murder, non-negligent manslaughter, and aggravated assault. Property crimes include arson, motor vehicle theft, larceny, and burglary. Statistics published by the Oregon Criminal Justice Commission showed a slight downward trend in the Washington County crime rate between 1991 and 2005. The rate for index crimes, a group comprising the combined violent offenses and property crimes mentioned above, was 3,930 per 100,000 in 1991 and rose to 4,440 per 100,000 in 1997 before falling to 3,410 per 100,000 in 2005.

For more than 150 years, the city has had residents as varied as David Hill, the city's founder, to Tiffeny Milbrett, an Olympic and World Cup champion soccer player. Two governors of Oregon, James Withycombe and Paul L. Patterson, have called the city home. Other politicians included Congressmen Thomas H. Tongue and Samuel Thurston; mayors William N. Barrett, Benjamin P. Cornelius, and William D. Hare, patriarch of the Hare political family. Athletes include Erik Ainge, Scott Brosius, Colt Lyerla, Ad Rutschman, Wes Schulmerich, Wally Backman, and Olympic medalists Josh Inman, Thomas Garrigus, and Jean Saubert. Hillsboro has also been home to Peggy Y. Fowler, the former chief executive officer of Portland General Electric, producer Bryce Zabel, the "Mother Queen of Oregon" Mary Ramsey Wood, Tommy Overstreet, and professional wrestler Roddy Piper.