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St. Joseph was founded on the Missouri River by Joseph Robidoux, a local fur trader, and officially incorporated in 1843. In its early days, it was a bustling outpost and rough frontier town, serving as a last supply point and jumping-off point on the Missouri River toward the "Wild West". It was the westernmost point in the United States accessible by rail until after the American Civil War.

The main east-west downtown streets were named for Robidoux's eight children: Faraon, Jules, Francois (Francis), Felix, Edmond, Charles, Sylvanie, and Messanie. The street between Sylvanie and Messanie was named for his second wife, Angelique.

St. Joseph, or "St. Joe", as it was called by many, was a "Jumping-Off Point" for those headed to the Oregon Territory in the mid-1800s. These cities, including Independence, and St. Joseph, were where pioneers would stay and purchase supplies before they would head out in wagon trains. The town was a very lively place, and was the second city in the US to have electric streetcars.^[when?]

Between April 3, 1860, and late October 1861, St. Joseph was one of the two endpoints of the Pony Express, which operated for a short period over the land then inaccessible by rail, to provide fast mail service. The pony riders carried additionally, along with the mail, a small personal Bible. Today the Pony Express Museum hosts visitors in the old stables.

On April 3, 1882 outlaw Jesse James was killed at his home, originally located at 1318 Lafayette, now sited next to the Patee House. In the post-Civil War years, when the economy was down, the hotel had served for a time as the home of the Patee Female College, followed by the St. Joseph Female College up to 1880. James was living under the alias of Mr. Howard. The song, "Jesse James", includes the lines, "...that dirty little coward that shot Mr. Howard has laid poor Jesse in his grave."

The Heaton-Bowman-Smith Funeral Home maintains a small museum about Jesse James. Their predecessors conducted the funeral. His home is now known as the Jesse James Home Museum. It has been relocated at least three times, and features the bullet hole from that fateful shot. St. Joseph is identified by the slogan, "Where the Pony Express started and Jesse James ended."

Among properties listed on the National Register of Historic Places are the Patee House, a former hotel now maintained as a museum of transportation, and the Missouri Theatre, an ornate movie palace.

St. Joseph's population peaked in 1900, with a census population of 102,979. This population figure is questionable, as civic leaders tried to inflate the numbers for that census. At the time, it was the home to one of the largest wholesale companies in the Midwest, the Nave & McCord Mercantile Company, as well as the Hannibal and St. Joseph Railroad, and the C.D. Smith & Company, which would become C.D. Smith Healthcare.

The Walnut Park Farm Historic District near St. Joseph was listed on the National Register of Historic Places in 1999.

In 1997, St. Joseph was named an "All-America City" by the National Civic League. St. Joseph was voted the top true western town of 2007 by True West Magazine, in the January/February 2008 issue.

On May 2, 2020, the city's local meat packaging plant run by Triumph Foods confirmed that 295 workers became infected with COVID-19 during the 2019–20 coronavirus pandemic. The next day 64 more cases were confirmed resulting in a total number of 359 infected workers. As of May 3,the case tally is currently at 373 infected workers. As of May 5, 412 workers were reported to have contracted the virus while showing no symptoms.

Saint Joseph is located at 39°45′29″N 94°50′12″W / 39.75806°N 94.83667°W / 39.75806; -94.83667 (39.757944, -94.836541), on the Missouri/Kansas border in northwestern Missouri, also close to Nebraska; Iowa is another 70 miles farther north. The nearest major metropolitan area to St. Joseph is the Kansas City Metropolitan Area, which begins approximately 30 miles (48 km) to the south. The nearest major airport is Kansas City International Airport, which is approximately 35 miles (56 km) to the south. According to the United States Census Bureau, the city has a total area of 44.77 square miles (115.95 km²), of which 43.99 square miles (113.93 km²) is land and 0.78 square miles (2.02 km²) is water.

The monthly weather averages listed below are taken from National Weather Service 1981-2010 Normals recorded at Rosecrans Airport. Because of the Airport's location near the Missouri River and at a low elevation, official overnight lows during wintertime especially are often several degrees colder than at other places within the city. Snowfall is not recorded at the St Joseph weather station although surrounding reporting stations typically receive 12-20 inches of snowfall annually.

As of the census of 2010, there were 76,780 people, 29,727 households, and 18,492 families residing in the city. The population density was 1,745.4 inhabitants per square mile (673.9/km²). There were 33,189 housing units at an average density of 754.5 per square mile (291.3/km²). The racial makeup of the city was 87.8% White, 6.0% Black, 0.5% Native American, 0.9% Asian, 0.2% Pacific Islander, 2.0% from other races, and 2.7% from two or more races. Hispanic or Latino of any race were 5.7% of the population.

There were 29,727 households, of which 32.0% had children under the age of 18 living with them, 42.0% were married couples living together, 14.5% had a female householder with no husband present, 5.7% had a male householder with no wife present, and 37.8% were non-families. 30.7% of all households were made up of individuals, and 12.2% had someone living alone who was 65 years of age or older. The average household size was 2.43 and the average family size was 3.01.

In the city, the population was spread out, with 23.6% under the age of 18; 11.7% between the ages of 18 and 24; 26.1% from 25 to 44; 24.9% from 45 to 64; and 13.8% who were 65 years of age or older. The median age in the city was 35.6 years. The gender makeup of the city was 49.8% male and 50.2% female.

As of the census of 2000, there were 73,990 people, 29,026 households, and 18,460 families residing in the city. The population density was 1,687.7 people per square mile (651.6/km²). There were 31,752 housing units at an average density of 724.2 per square mile (279.6/km²). The racial makeup of the city was 91.9% White, 5.0% Black, 0.5% Native American, 0.5% Asian, <0.1% Pacific Islander, 0.7% from other races, and 1.4% from two or more races. Hispanic or Latino of any race were 2.6% of the population.

There were 29,026 households, out of which 30.1% had children under the age of 18 living with them, 46.7% were married couples living together, 12.8% had a female householder with no husband present, and 36.4% were single-family households. 30.4% of all households were made up of individuals, and 13.2% had someone living alone who was 65 years of age or older. The average household size was 2.39 and the average family size was 2.98.

In the city, the population was spread out, with 24.1% under the age of 18, 11.6% from 18 to 24, 28.6% from 25 to 44, 20.3% from 45 to 64, and 15.4% who were 65 years of age or older. The median age was 36 years. For every 100 females, there were 95.6 males. For every 100 females age 18 and over, there were 92.7 males.

The median income for a household in the city was $32,663, and the median income for a family was $40,995. Males had a median income of $31,300 versus $21,592 for females. The per capita income for the city was $17,445. About 9.1% of families and 13.0% of the population were below the poverty line, including 15.5% of those under age 18 and 9.8% of those age 65 or over.