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Burial mounds in present-day Indian Mounds Park suggest the area was inhabited by the Hopewell Native Americans about 2,000 years ago. From the early 17th century to 1837, the Mdewakanton Dakota, a tribe of the Sioux, lived near the mounds after being displaced from their ancestral grounds by Mille Lacs Lake from advancing Ojibwe. The Dakota called the area Imniza-Ska ("white cliffs") for its exposed white sandstone cliffs on the river's eastern side. The Imniza-Ska were full of caves that were useful to the Dakota. The explorer Jonathan Carver documented the historic Wakan tipi in the bluff below the burial mounds in 1767. In the Menominee language St. Paul was called Sāēnepān-Menīkān, which means "ribbon, silk or satin village", suggesting its role in trade throughout the region after the introduction of European goods.

After the 1803 Louisiana Purchase, U.S Army Lieutenant Zebulon Pike negotiated approximately 100,000 acres (40,000 ha; 160 sq mi) of land from the indigenous Dakota in 1805 to establish a fort. A military reservation was intended for the confluence of the Mississippi and Minnesota rivers on both sides of the Mississippi up to Saint Anthony Falls. All of what is now the Highland park neighborhood was included in this. Pike planned a second military reservation at the confluence of the St. Croix and Mississippi rivers. In 1819 Fort Snelling was built at the Minnesota and Mississippi confluence. The 1837 Treaty with the Sioux ceded all tribal lands east of the Mississippi to the U.S. government.Chief Little Crow V moved his village, Kaposia, from south of Mounds Park across the river a few miles onto Dakota land. Fur traders, explorers, and settlers came to the area for the fort's security. Many were French-Canadians who predated American pioneers by some time. A whiskey trade flourished among the squatters and the fort's commander evicted them all from the fort's reservation. Fur trader turned bootlegger "Pig's Eye" Parrant, who set up business just outside the reservation, particularly irritated the commander. By the early 1840s, a community had developed nearby that locals called Pig's Eye (French: L'Œil du Cochon) or Pig's Eye Landing after Parrant's popular tavern. In 1842 a raiding party of Ojibwe attacked the Kaposia encampment south of St. Paul. A battle ensued where a creek drained into wetlands two miles south of Wakan Tipi. The creek was thereafter called Battle Creek and is today parkland. In the 1840s-70s the Métis brought their oxen and Red River Carts down Kellogg Street to Lambert's landing to send buffalo hides to market from the Red River of the North. St. Paul was the southern terminus of the Red River Trails. In 1840 Pierre Bottineau became a prominent resident with a claim near the settlement's center.

In 1841, Catholic missionary Lucien Galtier was sent to minister to the French Canadians at Mendota. He had a chapel he named for St. Paul built on the bluff above the riverboat landing downriver from Fort Snelling. Galtier informed the settlers that they were to adopt the chapel's name for the settlement and cease the use of "Pigs Eye". In 1847, New York educator Harriet Bishop moved to the settlement and opened the city's first school. The Minnesota Territory was created in 1849 with Saint Paul as the capital. The U.S. Army made the territory's first improved road, Point Douglas Fort Ripley Military Road, in 1850. It passed through what became St. Paul neighborhoods. In 1857, the territorial legislature voted to move the capital to Saint Peter, but Joe Rolette, a territorial legislator, stole the text of the bill and went into hiding, preventing the move. States were mandated to create militias to augment federal forces. St. Paul was the territory's first community to do so when it established the Pioneer Guard in 1856. On May 11, 1858, Minnesota gained statehood as the 32nd state, with Saint Paul its capital. When the Civil War broke out, the state learned Governor Ramsey had volunteered a regiment to fight the South. Communities across the state sent their militias as volunteers for the regiment. St. Paul sent its Pioneer Guard to form A and C Companies of the 1st Minnesota Volunteer Infantry.

The year 1858 saw more than 1,000 steamboats service Saint Paul, making it a gateway for settlers to the Minnesota frontier or Dakota Territory. Geography was a primary reason the city became a transportation hub. The location was the last good point to land riverboats coming upriver due to the river valley's topography. For a time, Saint Paul was called "The Last City of the East." Fort Snelling was important to St. Paul from the start. Direct access from St. Paul did not happen until the 7th bridge was built in 1880. Before that, there was a cable ferry crossing dating to at latest the 1840s. Once streetcars appeared, a new bridge to St. Paul was built in 1904. Until the town built its first jail the fort's brig served St. Paul.

Minnesota's first execution took place in St. Paul in 1860. A woman named Ann Bilansky was sentenced to hang. The state legislature voted to commute her sentence to life imprisonment, but Governor Ramsey vetoed that and issued her death warrant. She was the only woman ever hanged in the state. In 1906 the hanging of William Williams was botched in St. Paul, becoming a strangulation that took 14 minutes. The news of the botched execution brought an end to capital punishment in Minnesota.

Industrialist James J. Hill founded his railroad empire in St. Paul. The Great Northern Railway and the Northern Pacific Railway were both headquartered in St. Paul until they merged with the Burlington Northern. Today they are part of the BNSF Railway.

Prostitution was against both state and city law, but a system in St. Paul dating to 1863 made it quasi-legitimate. The madam of a brothel would appear in court once a month to pay a fine for operating a disorderly house. Post-Civil War St. Paul developed two districts of vice. The more infamous was "under the hill" on and around Eagle Street. In the 1870s the town had gained a reputation for being tough. It had twice Minneapolis's number of brothels, dozens more saloons, and one more brewery. By the mid-1880s it had 14 brothels and a few "cigar store" front operations. The city's most famous "high-end" madam was Nina Clifford. She ran her brothel until her death in 1929. A chandelier from it was mounted in the mayor's office when it was razed.

In 1887 the Minnesota Reserve National Guard was made the Guard's 3rd Infantry Regiment headquartered at the St. Paul Armory. Company C was made up of men from the city. For the Spanish-American War the Regiment was redesignated 14th Minnesota Volunteer Infantry. Company E was men from Merriam Park. The Spanish–American War saw the trans-Atlantic ocean liner SS St. Paul converted and commissioned into the United States Navy as an auxiliary cruiser. She was the first ship in the navy to bear the city's name. She was decommissioned and returned to her owners only to be conscripted again for WWI, after which she was again decommissioned and scrapped. When hostilities broke out with Spain, volunteers were requested from the states. Minnesota quickly had enough to form four units, the 12th-15th Minnesota Infantry Regiments. Of these, only the 13th was deployed to the Philippines. Companies C, D, E & H were from St. Paul and saw heavy combat in Manila.

In 1900 an Irishman, John O'Connor, became chief of the St. Paul police and was known on the street as "the Big Fellow". That year he instituted the "O'Connor Layover Agreement" and made an effort to inform criminals of its existence. St. Paul police would ignore any transgressions of the law that took place outside their jurisdiction as long as criminals "checked in" when they arrived in town. There were three conditions to the agreement: check in with the police; pay a "donation" to the chief; and commit no crimes in St. Paul. Check-in was at the Savoy Hotel downtown. A great deal of "business" was taken care of at the "Green Lantern" speakeasy near the train station in Lowertown. It was also known for illegal gaming. More got done in the caves across the river from downtown. In 1930 the local mob even arranged that St. Paul's new police chief would be Tom Brown. The "Agreement" lasted through the prohibition until 1935. In that time St. Paul welcomed Al Capone,John Dillinger, Billie Frechette, Ma Barker, Baby Face Nelson, Alvin Karpis, Machine Gun Kelly, Kid Cann and many of their Irish associates. To skirt the Layover rules Barker's gang resided a block outside of the city on Robert Street. Karpis said, “There was probably never before as complete a gathering of criminals in one room in the United States, as there was in the Green Lantern on New Year’s Eve in 1931. There were escapees from every U.S. Penitentiary. I was dazzled.”Bonnie and Clyde are also known to have called on the city. According to crime historian Paul Maccabee, the only criminal there is no record of visiting St. Paul during the Layover period is Pretty Boy Floyd. In 1933 the St. Paul police department closed St. Paul's doors to organized crime.

On August 20, 1904, severe thunderstorms and tornadoes damaged hundreds of downtown buildings, causing $1.78 million ($50.65 million today) in damages and ripping spans from the High Bridge.

Minnesota senator Andrew Volstead had his office in what is now the Landmark Center. In 1919 he wrote the Volstead Act there, which began Prohibition.

In 1920, a St. Paul councilman, the Commissioner of Safety, Aloysius Smith, asked the St. Paul Police to create a youth safety program for schools. At first it was just public schools, but program administrator Sergeant Frank Hetznecker went to the archdiocese to ask if the parochial schools wanted to be involved, and they did.Cathedral School headmistress Carmela Hanggi was a strong supporter of the program. In February 1921 the first student-monitored school patrol crossing took place on Kellogg Boulevard, by Cathedral students. The school patrol Sam Browne belt with badge that became synonymous with school patrol across the country came from the St. Paul program.

On the morning of December 7, 1941, the USS Ward was manned by reservists of Minnesota's naval militia. It had a crew of 115, of whom 85 were from St. Paul. That morning they were stationed at the entrance to Pearl Harbor. A periscope was sighted trailing a freighter and the Ward took action, becoming the first Americans to fire their weapons in WWII combat. The Ward's No. 3 gun is displayed on the State Capitol grounds. WWII saw the second USS St. Paul commissioned as a Baltimore-class cruiser. That ship's bell is on display in Saint Paul's city hall.

During the 1960s, in conjunction with urban renewal, Saint Paul razed neighborhoods west of downtown for the creation of the interstate freeway system. From 1959 to 1961, the Rondo Neighborhood was demolished for the construction of Interstate 94. The loss of that African American enclave brought attention to racial segregation and unequal housing in northern cities. The annual Rondo Days celebration commemorates the African American community.

Downtown St. Paul had skyscraper-building booms beginning in the 1970s. Because the city center is directly beneath the flight path into the airport across the river there is a height restriction for all construction. The tallest buildings, such as Galtier Plaza (Jackson and Sibley Towers), The Pointe of Saint Paul condominiums, and the city's tallest building, Wells Fargo Place (formerly Minnesota World Trade Center), were constructed in the late 1980s. In the 1990s and 2000s, the tradition of bringing new immigrant groups to the city continued. As of 2004, nearly 10% of the city's population were recent Hmong immigrants from Vietnam, Laos, Cambodia, Thailand, and Myanmar. Saint Paul is the location of the Hmong Archives.

The earliest known inhabitants from about 400 A.D. were members of the Hopewell tradition who buried their dead in mounds (now Indian Mounds Park) on the river bluffs. The next known inhabitants were the Mdewakanton Dakota in the 17th century who fled their ancestral home of Mille Lacs Lake in central Minnesota in response to westward expansion of the Ojibwe nation. The Ojibwe later occupied the north (east) bank of the Mississippi River.

By 1800, French-Canadian explorers came through the region and attracted fur traders to the area. Fort Snelling and Pig's Eye Tavern also brought the first Yankees from New England and English, Irish, and Scottish immigrants who had enlisted in the army and settled nearby after discharge. These early settlers and entrepreneurs built houses on the heights north of the river. The first wave of immigration came with the Irish, who settled at Connemara Patch along the Mississippi, named for their home, Connemara, Ireland. The Irish became prolific in politics, city governance, and public safety, much to the chagrin of the Germans and French who had grown into the majority. In 1850, the first of many groups of Swedish immigrants passed through Saint Paul on their way to farming communities in northern and western regions of the territory. A large group settled in Swede Hollow, which later became home to Poles, Italians, and Mexicans. The last Swedish presence moved up Saint Paul's East Side along Payne Avenue in the 1950s.

Of people who specified European ancestry in the 2005–07 American Community Survey of St. Paul, 26.4% were German, 13.8% Irish, 8.4% Norwegian, 7.0% Swedish, and 6.2% English. There is also a visible community of people of Sub-Saharan African ancestry, representing 4.2% of the population. By the 1980s, the Thomas-Dale area, once an Austro-Hungarian enclave known as Frogtown (German: Froschburg), became home to Vietnamese people who had left their war-torn country. A settlement program for the Hmong diaspora came soon after, and by 2000, the Saint Paul Hmong were the largest urban contingent in the United States. Mexican immigrants have settled in Saint Paul's West Side since the 1930s, and have grown enough that Mexico opened a foreign consulate in 2005.

The majority of residents claiming religious affiliation are Christian, split between the Roman Catholic Church and various Protestant denominations. The Roman Catholic presence comes from Irish, German, Scottish, and French Canadian settlers, who in time were bolstered by Hispanic immigrants. There are Jewish synagogues such as Mount Zion Temple and relatively small populations of Hindus, Muslims, and Buddhists. The city has been dubbed "paganistan" due to its large Wiccan population.

As of the 2005–07 American Community Survey, White Americans made up 66.5% of Saint Paul's population, of whom 62.1% were non-Hispanic whites, down from 93.6% in 1970.Blacks or African Americans made up 13.9% of the population, of whom 13.5% were non-Hispanic blacks. American Indians made up 0.8%, of whom 0.6% were non-Hispanic. Asian Americans made up 12.3%, of whom 12.2% were non-Hispanic. Pacific Islander Americans made up less than 0.1%. People of other races made up 3.4%, of whom 0.2% were non-Hispanic. Individuals from two or more races made up 3.1%, of whom 2.6% were non-Hispanic. In addition, Hispanics and Latinos made up 8.7%.

As of the 2000 U.S. Census, there were 287,151 people, 112,109 households, and 60,999 families residing in the city. The racial makeup of the city was 67.0% White, 11.7% African American, 1.1% Native American, 12.4% Asian (mostly Hmong), 0.1% Pacific Islander, 3.8% from other races, and 3.9% from two or more races. Hispanic or Latino people of any race were 7.9% of the population.

As of the 2010 census, there were 285,068 people, 111,001 households, and 59,689 families residing in the city. The population density was 5,484.2 inhabitants per square mile (2,117.5/km²). There were 120,795 housing units at an average density of 2,323.9 per square mile (897.3/km²). The racial makeup of the city was 60.1% white, 15.7% African American, 1.1% Native American, 15.0% Asian, 0.1% Pacific Islander, 3.9% from other races, and 4.2% from two or more races. Hispanic or Latino people of any race were 9.6% of the population.

There were 111,001 households, of which 30.4% had children under the age of 18 living with them, 34.1% were married couples living together, 14.8% had a female householder with no husband present, 4.9% had a male householder with no wife present, and 46.2% were non-families. 35.8% of all households were made up of individuals, and 8.5% had someone living alone who was 65 years of age or older. The average household size was 2.47 and the average family size was 3.33.

The median age in the city was 30.9 years. 25.1% of residents were under the age of 18; 13.9% were between the ages of 18 and 24; 29.6% were from 25 to 44; 22.6% were from 45 to 64; and 9% were 65 years of age or older. The gender makeup of the city was 48.9% male and 51.1% female.

Medal of Honor recipients: