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Prior to 1800, several hundred Senecas and other Iroquois tribes were the primary residents in the Buffalo area, concentrated along Buffalo Creek. The 1830s–1850s saw multitudes of working-class Irish and Germans from Europe, across rural New York and New England settle in the south and east sides of the city, respectively, preferring ethnocentric neighborhoods. At the turn of the 20th century, Polish immigrants replaced Germans on the east side, while Italian communities and families settled throughout the city, primarily on the lower west side. Puerto Ricans arrived en masse during the 1940s–1950s, settling on the east side and shifting westward, where they are to date. Since the 1970s, Buffalo has been mitigating the effects of urban decay, including populations losses to the suburbs and Sun Belt states, and job losses from its declining industrial base. The city's population grew until it peaked at 580,132 residents in 1950. At the time, Buffalo was the 15th largest city in the United States, down from the 8th largest in 1900 as the rate of growth slowed in the 1920s. The city's population started declining in the second half of 20th century due to suburbanization but began stabilizing in the 2010s. Buffalo had a population of 261,310 at the 2010 census and an estimated 255,284 residents in 2019.

Buffalo residents were generally intolerant of the small groups of Black Americans who began settling on the city's east side around the 1830s. Over one hundred years later, wartime and manufacturing jobs during the First and Second Great Migrations would attract many more Black Americans living in the South, and the city's black population rose by 433% from 1940 to 1970, replacing most of the Polish community on the east side. However, the combined effects of redlining, steering, social inequality, blockbusting, White flight and other racialized policies have resulted in the city and region ranking highly in segregation relative to other areas of the country. Today, Buffalo is a majority minority city whose residents are predominately Black and Latino Americans.

Compared to other major metropolitan areas in the country, the number of foreign-born immigrants to the city is low, but new immigrants have been disproportionately resettled refugees—especially those from war or disaster-afflicted nations, as well as those who previously settled in other U.S. cities. In the early 2000s, most immigrants came from Canada and Yemen, which shifted in the 2010s with Burmese (Karen) refugees and Indians immigrants. Burmese, Somali, Bhutanese, and Iraqi Americans were the four largest ethnic immigrant groups in Erie County from 2008–2016.

Poverty has remained a considerable issue for the city. In 2019, it was estimated that 30.1% of individuals and 24.8% of families were below the federal poverty line. Per capita income was measured at $24,400, and household income was $37,354, much less than the national average. A 2008 report noted that while food deserts are seen in larger cities and not in Buffalo, the city's neighborhoods of color have access to smaller grocery stores while lacking the supermarkets seen in white neighborhoods. A 2018 report revealed that over fifty city blocks on Buffalo's East Side lack adequate access to a supermarket. Compared to the rest of the state, Erie County ranked three years lower in average lifespan at 78.4 years old in 2019, with 17% smoking and 30% obesity rates, slightly higher than the state average. According to the Partnership for the Public Good, educational attainment in the city is lower than the surrounding area; city residents are almost twice as likely as adults in the metro area to lack a high school diploma.

Religion
In the early 19th century, Presbyterian missionaries tried to convert the native Seneca people at the Buffalo Creek Reservation to Christianity. Initially resistant, some tribal members set aside their traditions and practices to form their own branch of the sect. Later, European immigrants added other faiths. Today, Christianity is the predominant religion in Buffalo and Western New York. Catholicism, specifically the Latin Church has a large presence in the region, with 161 parishes and over 570,000 adherents in the Diocese of Buffalo. The Jewish community has had a presence in the city since the mid-1800s; approximately one thousand German and Lithuanian Jews settled in Buffalo prior to 1880. The first synagogue, Temple Beth El, was established in 1847; the city's Temple Beth Zion is the largest synagogue in the region. With the changing demographics and increase in the number of refugees on the city's East Side, religions such as Islam and Buddhism have expanded their presence, with former churches converted into mosques and temples. Hinduism maintains a small but active presence in the area, including in the town of Amherst. A 2016 American Bible Society survey claimed that Buffalo is the fifth-least "Bible-minded" city in the United States, with 13% of residents associating themselves with the Bible.