The first inhabitants of the New York State are believed to have been nomadic Paleo-Indians, who migrated after the disappearance of Pleistocene glaciers during or before 7000 BCE.

Around 1000 CE, the Woodland period began, marked by the rise of the Iroquois Confederacy and its tribes throughout the state.

During French exploration of the region in 1620, the region was occupied simultaneously by the agrarian Erie people, a tribe outside of the Five Nations of the Iroquois southwest of Buffalo Creek, and the Wenro people or Wenrohronon, an Iroquoian-speaking tribal offshoot of the large Neutral Nation who lived along the inland south shore of Lake Ontario and at the east end of Lake Erie and a bit of its northern shore. For trading, the Neutral people made a living by growing tobacco and hemp to trade with the Iroquois, using animal paths or warpaths to travel and move goods across the state. These paths were later paved, and now function as major roads.

Later, during the Beaver Wars of the 1640s-1650s, the combined warriors of the Five Nations of the Iroquois conquered the populous Neutrals and their peninsular territory, while the Senecas alone took out the Wenro and their territory, c. 1651–1653. Soon after, the Iroquois destroyed Erie nation and territory over their assistance to Huron people during the Beaver Wars.

Louis Hennepin and Sieur de La Salle made the earliest European discoveries of the upper Niagara and Ontario regions in the late 1600s. On August 7, 1679, La Salle launched a vessel, Le Griffon, that became the first full-sized ship to sail across the Great Lakes before it disappeared in Green Bay, Wisconsin.

After the American Revolution, the Province of New York—now a U.S. state—began westward expansion, looking for habitable land by following trends of the Iroquois. Land near fresh water was of considerable importance. New York and Massachusetts were fighting for the territory Buffalo lies on, and Massachusetts had the right to purchase all but a one-mile (1600-meter) wide portion of land. The rights to the Massachusetts' territories were sold to Robert Morris in 1791, and two years later to the Holland Land Company.

As a result of the war, in which the Iroquois tribe sided with the British Army, Iroquois territory was gradually reduced in the mid-to-late-1700s by European settlers through successive treaties statewide, such as the Treaty of Fort Stanwix (1784), the First Treaty of Buffalo Creek (1788), and the Treaty of Geneseo (1797). The Iroquois were corralled onto reservations, including Buffalo Creek. By the end of the 18th century, only 338 square miles (216,000 acres; 880 km²; 88,000 ha) of reservation territory remained.

The first white settlers along the creek were prisoners captured during the Revolutionary War. The first resident and landowner of Buffalo with a permanent presence was Captain William Johnston, a white Iroquois interpreter who had been in the area since the days after the Revolutionary War and who the Senecas granted creekside land as a gift of appreciation. His house stood at present-day Washington and Seneca streets. Former enslaved man Joseph "Black Joe" Hodges, and Cornelius Winney, a Dutch trader from Albany who arrived in 1789, were early settlers along the mouth of Buffalo Creek.

On July 20, 1793, the Holland Land Purchase was completed, containing the land of present-day Buffalo, brokered by Dutch investors from Holland. The Treaty of Big Tree removed Iroquois title to lands west of the Genesee River in 1797. In the fall of 1797, Joseph Ellicott, the architect who helped survey Washington, D.C. with brother Andrew, was appointed as the Chief of Survey for the Holland Land Company. Over the next year, he began to survey the tract of land at the mouth of Buffalo Creek. This was completed in 1803, and the new village boundaries extended from the creekside in the south to present-day Chippewa Street in the north and Carolina Street to the west, which is where most settlers remained for the first decade of the 19th century.^{[citation needed]} Although the company named the settlement "New Amsterdam," the name did not catch on, reverting to Buffalo within ten years. Buffalo had the first road to Pennsylvania built in 1802 for migrants passing through to the Connecticut Western Reserve in Ohio.

In 1804, Ellicott designed a radial grid plan that would branch out from the village forming bicycle-like spokes, interrupted by diagonals, like the system used in the nation's capital. In the middle of the village was the intersection of eight streets, in what would become Niagara Square. Several blocks to the southeast he designed a semicircle fronting Main Street with an elongated park green, formerly his estate. This would be known as Shelton Square, at that time the center of the city (which would be dramatically altered in the mid-20th century), with the intersecting streets bearing the names of Dutch Holland Land Company members, today Erie, Church and Niagara streets.Lafayette Square also lies one block to the north, which was then bounded by streets bearing Iroquois names.

According to an early resident, the village had sixteen residences, a schoolhouse and two stores in 1806, primarily near Main, Swan and Seneca streets. There were also blacksmith shops, a tavern and a drugstore. The streets were small at 40 feet wide, and the village was still surrounded by woods. The first lot sold by the Holland Land Company was on September 11, 1806, to Zerah Phelps. By 1808, lots would sell from $25 to $50.

In 1804, Buffalo's population was estimated at 400, similar to Batavia, but Erie County's growth was behind Chautauqua, Genesee and Wyoming counties. Neighboring village Black Rock to the northwest (today a Buffalo neighborhood) was also an important center. Horatio J. Spafford noted in A Gazetteer of the State of New York that in fact, despite the growth the village of Buffalo had, Black Rock "is deemed a better trading site for a great trading town than that of Buffalo," especially when considering the regional profile of mundane roads extending eastward. Before the east-to-west turnpike^{[further explanation needed]} was completed, travelling from Albany to Buffalo would take a week, while even a trip from nearby Williamsville to Batavia could take upwards of three days.

Although slavery was rare in the state, limited instances of slavery had taken place in Buffalo during the early part of the 19th century. General Peter Buell Porter is said to have had five slaves during his time in Black Rock, and several news ads also advertised slaves for sale.

In 1810, a courthouse was built. By 1811, the population was 500, with many people farming or doing manual labor. The first newspaper to be published was the Buffalo Gazette in October that same year.

On December 31, 1813, the British burned Buffalo and the village of Black Rock after the Battle of Buffalo. The battle and subsequent fire was in response to the unprovoked destruction of Niagara-on-the-Lake, then known as "Newark," by American forces. On August 4, 1814, British forces under Lt. Colonel John Tucker and Lt. Colonel William Drummond, General Gordon Drummond's nephew, attempted to raid Black Rock and Buffalo as part of a diversion to force an early surrender at Fort Erie the next day, but were defeated by a small force of American riflemen under Major Lodwick Morgan at the Battle of Conjocta Creek, and withdrew back into Canada. Consequently, Fort Erie's siege under Gordon Drummond later failed, and British forces withdrew. Though only three buildings remained in the village, rebuilding was swift, finishing in 1815.

The population in 1840 was 18,213. The village of Buffalo was part of and the seat of Niagara County until the legislature passed an act separating them on April 2, 1861.

On October 26, 1825, the Erie Canal was completed, formed from part of Buffalo Creek, with Buffalo a port-of-call for settlers heading westward. At the time, the population was about 2,400. By 1826, the 130 sq. mile Buffalo Creek Reservation at the western border of the village was transferred to Buffalo. The Erie Canal brought a surge in population and commerce, which led Buffalo to incorporate as a city in 1832. The canal area was mature by 1847, with passenger and cargo ship activity leading to congestion in the harbor.

The mid-1800s saw a population boom, with the city doubling in size from 1845 to 1855. In 1855, almost two-thirds of the city's population were foreign-born immigrants, largely a mix of unskilled or educated Irish and German Catholics, who began self-segregating in different parts of the city. The Irish immigrants planted their roots along the railroad-heavy Buffalo River and Erie Canal to the southeast, to which there is still a heavy presence today; German immigrants found their way to the East Side, living a more laid-back, residential life. Some immigrants were apprehensive about the change of environment and left the city for the western region, while others tried to stay behind in the hopes of expanding their native cultures.

Fugitive black slaves began to make their way northward to Buffalo in the 1840s, and many settled on the city's East Side. In 1845, construction began on the Macedonia Baptist Church, a meeting spot in the Michigan and William Street neighborhood where blacks first settled. Political activity surrounding the anti-slavery movement took place in Buffalo during this time, including conventions held by the National Convention of Colored Citizens and the Liberty Party and its offshoots. Buffalo was a terminus point of the Underground Railroad with many fugitive slaves crossing the Niagara River to Fort Erie, Ontario in search of freedom.

During the 1840s, Buffalo's port continued to develop. Both passenger and commercial traffic expanded with some 93,000 passengers heading west from the port of Buffalo.^{[better source needed]} Grain and commercial goods shipments led to repeated expansion of the harbor.^{[citation needed]} In 1843, the world's first steam-powered grain elevator was constructed by local merchant Joseph Dart and engineer Robert Dunbar. "Dart's Elevator" enabled faster unloading of lake freighters along with the transshipment of grain in bulk from barges, canal boats, and rail cars. By 1850, the city's population was 81,000.

In 1860, many railway companies and lines crossed through and terminated in Buffalo. Major ones were the Buffalo, Bradford and Pittsburgh Railroad (1859), Buffalo and Erie Railroad and the New York Central Railroad (1853). During this time, Buffalonians controlled a quarter of all shipping traffic on Lake Erie, and shipbuilding was a thriving industry for the city.

Later, the Lehigh Valley Railroad would have its line terminate at Buffalo in 1867.

At the dawn of the 20th century, local mills were among the first to benefit from hydroelectric power generated by the Niagara River. The city got the nickname The City of Light at this time due to the widespread electric lighting. It was also part of the automobile revolution, hosting the brass era car builders Pierce Arrow and the Seven Little Buffaloes early in the century. At the same time, an exit of local entrepreneurs and industrial titans brought about a nascent stage that would see the city lose its competitiveness against Pittsburgh, Cleveland and Detroit.

President William McKinley was shot and mortally wounded by an anarchist at the Pan-American Exposition in Buffalo on September 6, 1901. McKinley died eight days later and Theodore Roosevelt was sworn in at the Wilcox Mansion. The Great Depression of 1929–39 saw severe unemployment, especially among working-class men. The New Deal relief programs operated full force. The city became a stronghold of labor unions and the Democratic Party.

During World War II, Buffalo saw the return of prosperity and full employment due to its position as a manufacturing center. As one of the most populous cities of the 1950s, Buffalo's economy revolved almost entirely on its manufacturing base. Major companies such as Republic Steel and Lackawanna Steel employed tens of thousands of Buffalonians. Integrated national shipping routes would use the Soo Locks near Lake Superior and a vast network of railroads and yards that crossed the city.

Lobbying by local businesses and interest groups against the St. Lawrence Seaway began in the 1920s, long before its construction in 1957, which cut the city off from valuable trade routes. Its approval was reinforced by legislation shortly before its construction. Shipbuilding in Buffalo, such as the American Ship Building Company, shut down in 1962, ending an industry that had been a sector of the city's economy since 1812, and a direct result of reduced waterfront activity. With deindustrialization, and the nationwide trend of suburbanization; the city's economy began to deteriorate. Like much of the Rust Belt, Buffalo, home to more than half a million people in the 1950s, has seen its population decline as heavy industries shut down and people left for the suburbs or other cities.

Like most former industrial cities of the Great Lakes region in the United States, Buffalo is recovering from an economic depression from suburbanization and the loss of its industrial base. The city's population peaked in 1950 when it was the 15th largest city in the United States, down from the 8th largest city in America in 1900, and its population has been spreading out to the suburbs every census since then. In 2010, Buffalo had a population of 261,310 and an estimated 255,284 inhabitants in 2019. The city's median household income was $24,536 and the median family income was $30,614 in 2010. Males had a median income of $30,938 versus $23,982 for females. The city's per capita income was $14,991. Of the population, 26.6% of individuals and 23% of families, were below the poverty line. Of the total population, 38.4% of those under 18 and 14% of those over 65 were living below the poverty line. The U.S. Census Bureau determined the median household income in 2018 was $35,893 and the per capita income was $23,297. Of the population, 30.3% lived at or below the poverty line in 2018.

Common to many U.S. cities from the 1950s to the 1990s, Buffalo has become a diverse city. The city's diversification is due in part to white flight, the Great Migration, and immigration. Since 2015, Buffalo has become a majority-minority city primarily dominated by African Americans and Hispanic or Latin Americans.

At the American Community Survey's 2018 estimates, 42.5% of the population was non-Hispanic white, 34.3% African American, 0.3% American Indian or Alaska Native, 6.5% Asian, 0.1% from some other race and 3.3% from two or more races. Approximately 13% of Buffalonians were of Hispanic or Latin American origin. The largest Latin American groups in 2018 were Puerto Ricans (9.7%), Mexicans (0.7%), and Cubans (0.3%). Since 2003, there has been an ever-growing number of Burmese refugees, mostly of the Karen ethnicity, with an estimated 4,665 residing in Buffalo as of 2016. In 2018, 10% of the population were foreign-born. At the 2010 census, the city's population was 50.4% white (45.8% non-Hispanic white), 38.6% black or African-American, 0.8% American Indian and Alaska Native, 3.2% Asian, 3.9% from some other race and 3.1% from two or more races, while 10.5% of the population was Hispanic or Latino of any race.

Per Sperling's BestPlaces in 2020, nearly 60% of Buffalonians identify with a religion. Overall, Buffalo and Upstate New York are more religious than Downstate New York.

Largely a result of British and French colonialism and missionary work, Christianity is the largest religion in Buffalo and Western New York. The largest Christian groups in Buffalo and the surrounding area are the Catholic Church (38.8%) and Baptists (2.9%). Buffalo's Catholic population primarily make up the Latin Church's Diocese of Buffalo. The Catholic Diocese of Buffalo covers Western New York except for the nearby Diocese of Rochester. Its episcopal see is St. Joseph Cathedral. Baptists in the city mainly affiliate with the American Baptist Churches USA,National Baptist Convention, USA and the National Baptist Convention of America. There is one Cooperative Baptist church within the metropolitan area as of 2020. The third largest Christian group in the city are Lutherans (2.7%), primarily served by the Evangelical Lutheran Church in America.

Methodists (2.0%), Presbyterians (1.9%) and Pentecostals (1.2%) were the following largest Christian groups. The Methodist and Presbyterian Buffalonian communities are dominated by the United Methodist Church and Presbyterian Church (USA). Pentecostals are generally affiliated with the Assemblies of God USA and Church of God in Christ.

Nearly 1% of local Christians identified as Anglican or Episcopalian. Most align themselves with the Diocese of Western New York of the Episcopal Church in the U.S. Its cathedral is St. Paul's Cathedral. The remainder are affiliated with Continuing Anglican or Evangelical Episcopal denominations. There are two Anglican Church in North America-affiliated churches further east in the Rochester metropolitan area.

Approximately 0.3% professed Mormonism and 3.3% were of another Christian faith including the Eastern Orthodox and Oriental Orthodox churches, non-denominational Protestants, and others. The largest Eastern Orthodox jurisdictions are the Greek Orthodox Archdiocese of America (Ecumenical Patriarchate) and Diocese of New York and New Jersey (Orthodox Church in America).

Islam is Buffalo's second largest religion (1.8%). Sunni Islam is the predominant branch practiced. Most Sunni mosques are members of the Islamic Society of North America. The Nation of Islam has one mosque in Buffalo.

Judaism made up the third largest religion in the area (0.9%). As of 2020, Orthodox, Conservative, and Reform Judaism were the most prevalent groups affiliated with throughout Buffalo and the surrounding area. A little over 0.5% professed an eastern faith including Buddhism, Hinduism, and Sikhism.

The remainder of Buffalo and the surrounding area was spiritual but not religious, agnostic, deistic or atheist, though some Buffalonians identified with contemporary pagan religions including Wicca, Nature religion and other smaller new religious movements. Many contemporary pagans, spiritual but not religious and New Age residents attend the city's Winter Solstice celebrations annually. They are also participants of the Western New York Pagan Pride celebrations.