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Framingham, sited on the ancient trail known as the Old Connecticut Path, was first settled by a European when John Stone settled on the west bank of the Sudbury River in 1647. Native American leader Tantamous lived in the Nobscot Hill area of Framingham prior to King Philip's War in 1676. In 1660, Thomas Danforth, an official of the Bay Colony, formerly of Framlingham, Suffolk, received a grant of land at "Danforth's Farms" and began to accumulate over 15,000 acres (100 km²). He strenuously resisted petitions for incorporation of the town, which was officially incorporated in 1700, following his death the previous year. Why the "L" was dropped from the new town's name is not known. The first church was organized in 1701, the first teacher was hired in 1706, and the first permanent schoolhouse was built in 1716.

On February 22, 1775, the British general Thomas Gage sent two officers and an enlisted man out of Boston to survey the route to Worcester, Massachusetts. In Framingham, those spies stopped at Buckminster's Tavern. They watched the town militia muster outside the building, impressed with the men's numbers but not their discipline. Though "the whole company" came into the tavern after their drill, the officers remained undetected and continued on their mission the next day. Gage did not order a march along that route, instead ordering troops to Concord, Massachusetts, on April 18–19. Framingham sent two militia companies totaling about 130 men into the Battles of Lexington and Concord that followed; one of those men was wounded.

In the years before the American Civil War, Framingham was an annual gathering-spot for members of the abolitionist movement. Each Independence Day from 1854 to 1865, the Massachusetts Anti-Slavery Society held a rally in a picnic area called Harmony Grove near what is now downtown Framingham. At the 1854 rally, William Lloyd Garrison burned copies of the Fugitive Slave Law of 1850, judicial decisions enforcing it, and the United States Constitution. Other prominent abolitionists present that day included William Cooper Nell, Sojourner Truth, Wendell Phillips, Lucy Stone, and Henry David Thoreau.

During the post-World War II baby boom, Framingham, like many other suburban areas, experienced a large increase in population and housing. Much of the housing constructed during that time consisted of split-level and ranch-style houses.

Framingham is known for the Framingham Heart Study, as well as for the Dennison Manufacturing Company, which was founded in 1844 as a jewelry and watch box manufacturing company by Aaron Lufkin Dennison, who became the pioneer of the American System of Watch Manufacturing at the nearby Waltham Watch Company. His brother Eliphalet Whorf Dennison developed the company into a sizable industrial complex which merged in 1990 into Avery Dennison, with headquarters in Pasadena, California, and active corporate offices in the town.

In 2000, Framingham celebrated its Tercentennial. Framingham soon rose to become the largest town in Massachusetts, commonly referred to by the people of Framingham as "The largest town in the country." Framingham had attempted to become a city on three prior occasions 1993, 1997, and 2013, all of which were rejected by the people of Framingham. However, on January 1, 2018, Framingham became a city and Yvonne M. Spicer was inaugurated as its first mayor, thus becoming the first popularly elected African-American female mayor in Massachusetts.

As of the census of 2010, there were 68,318 people, 26,173 households, and 16,535 families residing in the city. The population density was 2,732.7 people per square mile (1,054.3/km²). There were 27,529 housing units, of which 1,356, or 4.9%, were vacant. The racial makeup of the city was 71.9% White, 5.8% Black, 0.3% Native American, 6.3% Asian, 0.1% Pacific Islander, 10.9% from some other race, and 4.6% from two or more races. Hispanic or Latino of any race were 13.4% of the population (4.7% Puerto Rican, 1.8% Guatemalan, 1.5% Salvadoran, 1.1% Dominican, 0.9% Mexican, 0.6% Colombian, 0.3% Peruvian). (Source: 2010 Census Quickfacts)

Of the 26,173 households, 31.1% had children under the age of 18 living with them, 48.2% were headed by married couples living together, 10.8% had a female householder with no husband present, and 36.8% were non-families. 28.4% of all households were made up of individuals, and 10.0% were someone living alone who was 65 years of age or older. The average household size was 2.47, and the average family size was 3.03.

As of 2010, 20.9% of the population were under the age of 18, 9.8% were from 18 to 24, 30.0% were from 25 to 44, 25.8% were from 45 to 64, and 13.6% were 65 years of age or older. The median age was 38.0 years. For every 100 females, there were 93.5 males. For every 100 females age 18 and over, there were 90.8 males.

In 2017, the estimated median income for a household in the city was $84,050, and the median income for a family was $101,078. Male full-time workers had a median income of $61,659, versus $54,714 for females. The per capita income for the city was $38,917. About 7.5% of families and 11.2% of the population were below the poverty line, including 12.7% of those under age 18 and 9.4% of those age 65 or over.

Brazilian immigrants have a major presence in Framingham. Since the 1980s, a large segment of the Brazilian population has come from the single city of Governador Valadares.