Utica was established on the site of Old Fort Schuyler, built by American colonists for defense in 1758 during the French and Indian War, the North American front of the Seven Years' War against France. Prior to construction of the fort, the Mohawk, Onondaga and Oneida tribes had occupied this area south of the Great Lakes region as early as 4000 BC. The Mohawk were the largest and most powerful tribe in the eastern part of the Mohawk Valley. American colonists had a longstanding fur trade with them, in exchange for firearms and rum. The tribe's dominating presence in the region prevented the Province of New York from expanding past the middle of the Mohawk Valley until after the American victory in the Revolutionary War, when the British-allied Iroquois were forced to cede their lands as allies of the defeated British, and the American-allied Iroquois were forced to cede land in exchange for shelter and supplies following brutal fighting.

The land housing Old Fort Schuyler was part of a 20,000-acre (81 km²) portion of marshland granted by King George II to New York governor William Cosby on January 2, 1734. Since the fort was located near several trails (including the Great Indian Warpath), its position—on a bend at a shallow portion of the Mohawk River—made it an important fording point. The Mohawk called the bend Unundadages ("around the hill"), and the Mohawk word appears on the city's seal.

During the American Revolutionary War, border raids from British-allied Iroquois tribes harried the settlers on the frontier. George Washington ordered Sullivan's Expedition, Rangers, to enter Central New York and suppress the Iroquois threat. More than 40 Iroquois villages were destroyed and their winter stores, causing starvation. In the aftermath of the war, numerous European-American settlers migrated into the state and this western region from New England, especially Connecticut.

In 1794 a state road, Genesee Road, was built from Utica west to the Genesee River. That year a contract was awarded to the Mohawk Turnpike and Bridge Company to extend the road northeast to Albany, and in 1798 it was extended. The Seneca Turnpike was key to Utica's development, replacing a worn footpath with a paved road. The village became a rest and supply area along the Mohawk River for goods and the many people moving through Western New York to and from the Great Lakes.

The boundaries of the village of Utica were defined in an act passed by the New York State Legislature on April 3, 1798. Utica expanded its borders in subsequent 1805 and 1817 charters. On April 5, 1805, the village's eastern and western boundaries were expanded, and on April 7, 1817, Utica separated from Whitestown on its west. After completion of the Erie Canal in 1825, the city's growth was stimulated again.

The municipal charter was passed by the state legislature on February 13, 1832. The city's growth during the 19th century is indicated by the increase in its population; in 1845 the United States Census ranked Utica as the 29th-largest in the country (with 20,000 residents, more than the populations of Chicago, Detroit or Cleveland.)

Utica's location on the Erie and Chenango canals encouraged industrial development, allowing the transport of anthracite from northeastern Pennsylvania for local manufacturing and distribution. Utica's economy centered around the manufacture of furniture, heavy machinery, textiles and lumber. The combined effects of the Embargo Act of 1807 and local investment enabled further expansion of the textile industry. Like other upstate New York cities, mills in Utica processed cotton from the Deep South, produced by slave labor.

In addition to the canals, transport in Utica was bolstered by railroads running through the city. The first was the Mohawk and Hudson Rail Road, which became the Utica and Schenectady Railroad in 1833. Its 78-mile (126 km) connection between Schenectady and Utica was developed in 1836 from the right-of-way previously used by the Mohawk and Hudson River railway. Later lines, such as the Syracuse and Utica Railroad, merged with the Utica and Schenectady to form the New York Central Railroad, which originated as a 19th-century forest railway in the Adirondacks.

During the 1850s, Utica aided more than 650 fugitive slaves; it played a major role as a station in the Underground Railroad. The city was on a slave escape route from the Southern Tier to Canada by way of Albany, Syracuse, and Rochester. The route, used by Harriet Tubman to travel to Buffalo, guided slaves to pass through Utica on the New York Central Railroad right-of-way en route to Canada. Utica was the locus for Methodist preacher Orange Scott's antislavery sermons during the 1830s and 1840s, and Scott formed an abolitionist group there in 1843. The 1835 initial meeting of the New York Anti-Slavery Society, in Utica, was disrupted by an anti-abolitionist mob, including local congressman Samuel Beardsley and other "prominent citizens". (It adjourned to Gerrit Smith's home in nearby Peterboro, New York).

The early 20th century brought rail advances to Utica, with the New York Central electrifying 49 miles (79 km) of track from the city to Syracuse in 1907 for its West Shore interurban line. In 1902, the Utica and Mohawk Valley Railway connected Rome to Little Falls with a 37.5-mile (60.4 km) electrified line through Utica.

By the 1950s, Utica was known as "Sin City" because of the extent of its corruption at the hands of the Democratic Party political machine. During the late 1920s, trucker Rufus Elefante rose to power although he never ran for office. Originally a Republican, Elefante's power was enhanced by support from New York governor Franklin D. Roosevelt. Waves of Italian, Irish, Polish and Lebanese Maronite immigrants worked in the city's industries in the early part of the 20th century. Until the 1980s, organized crime had a strong role in the city.

Strongly affected by the deindustrialization that took place in other Rust Belt cities, Utica suffered a major reduction in manufacturing activity during the second half of the 20th century. The 1954 opening of the New York State Thruway (which bypassed the city) and declines in activity on the Erie Canal and railroads throughout the United States also contributed to a poor local economy. During the 1980s and 1990s, major employers such as General Electric and Lockheed Martin began to close plants in Utica and Syracuse.

City jobs were moved to the towns and villages around Utica during the suburbanization of the postwar period. This led to the expansion of the nearby Town of New Hartford and the village of Whitesboro. Utica's lack of quality academic and educational choices, when compared to Syracuse under an hour away, contributed to its decline in local businesses and jobs as some economic activity moved to Syracuse during the 1990s. Utica's population fell while population in the county increased, reflecting a statewide trend of decreasing urban populations outside New York City. Residents who remain in the city struggle to handle poverty issues stemming from social and economic conditions caused partially by a smaller tax base; this adversely affects schools and public services. Despite the city's economic decline, it has benefited from a low cost of living, attracting immigrants and refugees from around the world.

In 2010, Utica, the focus of local, regional and statewide economic-revitalization efforts, developed its first comprehensive master plan in more than a half-century.

The city's growth during the 19th century is indicated by the increase in its population; in 1845 the United States Census ranked Utica as the 29th-largest in the country (with 20,000 residents, more than the populations of Chicago, Detroit or Cleveland.)

Today, the city is the tenth-most populous in New York and the sixth-most populous metro region in New York. It is the seat of Oneida County, and (with Schenectady) a focal point of the six-county Greater Mohawk Valley region. According to a U.S. Census estimate, the Utica–Rome Metropolitan Statistical Area decreased in population from 299,397 in 2010 to 296,615 on July 1, 2014 and its population density was about 3,818 people per square mile (1,474/km²). Counties in the Greater Mohawk Valley have a combined population of 622,133.

Utica's population has remained ethnically diverse and has received many new influxes of immigrants since the 1990s. New immigrants and refugees have included Bosnians (displaced by the Bosnian War), Burmese, Latinos, Russians, and Vietnamese. More than 42 languages are spoken in the city. Utica's population halted a forty-year decline in 2010, influenced by this influx of refugees and immigrants. Utica has a low cost of living but its industrial and economic decline have posed difficulties for people trying to make a new start.

In the 2010 United States Census, Utica's population was 62,235. According to the 2013 American Community Survey, Italian Americans have shrunk over the years, having once comprised at least 40% of the city. Italian Americans however remain the most prominent ethnic group, constituting (20%) of the city population and remaining the major traditional voting block, strongly favouring the Democratic Party.

The remainder of sizable ethnic groups include, as approximations: Slavs (18%) broken down as Poles (8.3%), Bosnians (7%) and Eastern Slavs at a combined (2.7%). Irish (11.3%), African Americans (10.5%), German (10.3%), ethnically English or American residents (8%), Puerto Ricans (6.8%). Burmese (3.5%), French and French-Canadians (2.7%), Arabs and Lebanese (2%), (non-Hispanic) Caribbean West Indies (1.8%), Dominicans (1.5%), Vietnamese (1.5%) and Cambodians (.7%). Iroquois or other (non-Hispanic) Amerindians (.3%).

Median income per Utica household was $30,818. Per capita income was $17,653, and 29.6 percent of the population were below the poverty threshold.

According to the current US Census conventions on Race, the population is broken down as: