The origin of the city's name is unclear, but the most common view is that it was named for Springfield, Massachusetts, by migrants from that area. One account holds that James Wilson, who lived in the then unnamed city, offered free whiskey to anyone who would vote for the name Springfield, after his hometown in Massachusetts.

The editor of the Springfield Express, J. G. Newbill, said in the November 11, 1881 issue:

In 1883, historian R. I. Holcombe wrote:

The presence of the Native Americans in the area slowed the European-American settlement of the land. Long before the 1830s, the native Kickapoo and Osage, and the Lenape (Delaware) from the mid-Atlantic coast had settled in this general area. The Osage had been the dominant tribe for more than a century in the larger region.

On the southeastern side of the city in 1812, about 500 Kickapoo Native Americans built a small village of about 100 wigwams. They abandoned the site in 1828. Ten miles south of the site of Springfield, the Lenape had built a substantial dwelling of houses that borrowed elements of Anglo colonial style from the mid-Atlantic, where their people had migrated from.

The first European-American settlers to the area were John Polk Campbell and his brother, who moved to the area in 1829 from Tennessee. Campbell chose the area because of the presence of a natural well that flowed into a small stream. He staked his claim by carving his initials in a tree. Campbell was joined by settlers Thomas Finney, Samuel Weaver, and Joseph Miller. They proceeded to clear the land of trees to develop it for farms. A small general store was soon opened.

In 1833, the southern part of the state was named Greene County after Revolutionary War hero General Nathanael Greene. The legislature deeded 50 acres of land to John Campbell for the creation of a county seat in 1835. Campbell laid out city streets and lots. The town was incorporated in 1838. In 1878, the town got its nickname the "Queen City of the Ozarks."

The United States government enforced Indian Removal during the 1830s, forcing land cessions in the Southeast and other areas, and relocating tribes to Indian Territory, which later developed as Oklahoma. During the 1838 relocation of Cherokee natives, the Trail of Tears passed through Springfield to the west, along the Old Wire Road.

By 1861, Springfield's population had grown to approximately 2,000, and it had become an important commercial hub. In the late 1850s, telegraph lines, previously only to St. Louis, reached Springfield. News from point further west was brought to Springfield overland and then sent by telegraph to what was then called the New York Associated Press. At the start of the American Civil War, Springfield was divided in its loyalty, as it had been settled by people from both the North and South, as well as by German immigrants in the mid-19th century who tended to support the Union.

The Union and Confederate armies both recognized the city's strategic importance and sought to control it. They fought the Battle of Wilson's Creek on August 10, 1861, a few miles southwest of town. The battle was a Confederate victory, and Nathaniel Lyon became the first Union General killed in Civil War. Union troops retreated to Lebanon to regroup. When they returned, they found that most of the Confederate army had withdrawn.

On October 25, 1861, Union Major Charles Zagonyi led an attack against the remaining Confederates in the area, in a battle known as the First Battle of Springfield, or Zagonyi's Charge. Zagonyi's men removed the Confederate flag from Springfield's public square and returned to camp. It was the only Union victory in southwestern Missouri in 1861. The increased military activity in the area set the stage for the Battle of Pea Ridge in northern Arkansas in March 1862.

On January 8, 1863, Confederate forces under General John S. Marmaduke advanced to take control of Springfield and an urban fight ensued. But that evening, the Confederates withdrew. This became known as the Second Battle of Springfield. Marmaduke sent a message to the Union forces asking that the Confederate casualties have a proper burial. The city remained under Union control for the remainder of the war. The US army used Springfield as a supply base and central point of operation for military activities in the area.

Promptly after the Civil War ended on July 21, 1865 Wild Bill Hickok shot and killed Davis Tutt in a shootout over a disagreement about a debt Tutt claimed Hickok owed him. During a poker game at the former Lyon House Hotel, in response to the disagreement over the amount, Tutt had taken Hickok's watch, which Hickok demanded he return immediately. Hickok warned that Tutt had better not be seen wearing that watch, then spotted him wearing it in Park Central Square, prompting the gunfight.

On January 25, 1866, Hickok was still in Springfield when he witnessed a Springfield police officer, John Orr, shoot and kill James Coleman after Coleman interfered with the arrest of Coleman's friend Bingham, who was drunk and disorderly. Hickok provided testimony in the case. Orr was arrested, released on bail, and immediately fled the country. He was never brought to trial or heard from again.

The period after Reconstruction and into the early 20th century continued to be socially volatile, with whites attacking blacks in the South. Some cities and counties in Missouri, particularly in former slaveholding areas, also had lynchings of freedmen and their descendants.

On April 14, 1906, a white mob broke into the Springfield county jail, and lynched two black men, Horace Duncan and Fred Coker, for allegedly sexually assaulting Mina Edwards, a white woman. Later they returned to the jail, where other African-American prisoners were being held, and pulled out Will Allen, who had been accused of murdering a white man. All three suspects were hanged from the Gottfried Tower, which held a replica of the Statue of Liberty, and burned in the courthouse square by a mob of more than 2,000 citizens. Judge Azariah W. Lincoln called for a grand jury, but no one was prosecuted. The proceedings were covered by national newspapers, the New York Times and Los Angeles Times.

Duncan's and Coker's employer testified that they were at his business at the time of the crime against Edwards, and other evidence suggested that they and Allen were all innocent. These three are the only recorded lynchings in Greene County. But the extrajudicial murders were part of a pattern of discrimination, repeated violence and intimidation of African Americans in this city and southwest Missouri from 1894 to 1909, in an attempt to expel them from the region. Whites in Lawrence County also lynched three African-American men in this period. After the mass lynching in Springfield, many African Americans left the area in a large exodus.

In the 21st century, the African American population has experienced steady minority growth in Springfield and throughout the Ozarks. A historic plaque on the southeast corner of the Springfield courthouse square commemorates Duncan, Coker, and Allen, the three victims of mob violence.

During the 1950s, Springfield ranked third in the U.S. for originating network television programs, behind New York and Hollywood^{[citation needed]}. Four nationally broadcast television series originated from the city between 1955 and 1961: Ozark Jubilee and its spin-off, Five Star Jubilee; Talent Varieties; and The Eddy Arnold Show. All were carried live by ABC except for Five Star Jubilee on NBC and were produced by Springfield's Crossroads TV Productions, owned by Ralph D. Foster. Many of the biggest names in country music frequently visited or lived in Springfield at the time. City officials estimated the programs meant about 2,000 weekly visitors and "over $1,000,000 in fresh income."

Staged at the Jewell Theatre (demolished in 1961), Ozark Jubilee was the first national country music TV show to feature top stars and attract a significant viewership. Five Star Jubilee, produced from the Landers Theatre, was the first network color television series to originate outside of New York City or Hollywood. Ironically, Springfield's NBC affiliate, KYTV-TV (which helped produce the program), was not equipped to broadcast in color and aired the show in black-and-white.

The ABC, NBC and Mutual radio networks also all carried country music shows nationally from Springfield during the decade, including KWTO'S Korn's-A-Krackin' (Mutual).

The Springfield Chamber of Commerce once presented visiting dignitaries with an "Ozark Hillbilly Medallion" and a certificate proclaiming the honoree a "hillbilly of the Ozarks." On June 7, 1953, U.S. President Harry Truman received the medallion after a breakfast speech at the Shrine Mosque for a reunion of the 35th Division. Other recipients included US Army generals Omar Bradley and Matthew Ridgway, US Representative Dewey Short, J. C. Penney, Johnny Olson, Ralph Story and disc jockey Nelson King.

As of the 2010 census, there were 159,498 people, 69,754 households, and 35,453 families residing in the city. The population density was 1,951.8 inhabitants per square mile (753.6/km²). There were 77,620 housing units at an average density of 949.8 per square mile (366.7/km²). The racial makeup of the city was 88.7% White, 4.1% African American, 0.8% Native American, 1.9% Asian, 0.2% Pacific Islander, 1.2% from other races, and 3.2% from two or more races. Hispanic or Latino of any race were 3.7% of the population.

There were 69,754 households, of which 23.4% had children under the age of 18 living with them, 34.4% were married couples living together, 11.8% had a female householder with no husband present, 4.7% had a male householder with no wife present, and 49.2% were non-families. 37.3% of all households were made up of individuals, and 11.8% had someone living alone who was 65 years of age or older. The average household size was 2.13 and the average family size was 2.81.

The median age in the city was 33.2 years. 18.3% of residents were under the age of 18; 18.4% were between the ages of 18 and 24; 26% were from 25 to 44; 22.7% were from 45 to 64; and 14.5% were 65 years of age or older. The gender makeup of the city was 48.5% male and 51.5% female.

According to the 2000 United States Census, 151,580 people, 64,691 households, and 35,709 families resided in the city. The population density was 2,072.0 people per square mile (800.0/km²). There were 69,650 housing units at an average density of 952.1/mi² (367.6/km²). The racial makeup of the city was 91.69% White, 3.27% African American, 0.75% Native American, 1.36% Asian, 0.09% Pacific Islander, 0.88% from other races, and 1.95% from two or more races. Hispanic or Latino of any race were 2.31% of the population.

There were 64,691 households, out of which 24.0% had children under the age of 18 living with them, 40.7% were married couples living together, 10.9% had a female householder with no husband present, and 44.8% were non-families. 35.3% of all households were made up of individuals, and 11.6% had someone living alone who was 65 years of age or older. The average household size was 2.17 and the average family size was 2.82. In the city 19.9% were under the age of 18, 17.4% from 18 to 24, 28.0% from 25 to 44, 19.8% from 45 to 64, and 14.9% were 65 years of age or older. The median age was 34 years. For every 100 females, there were 92.9 males. For every 100 females age 18 and over, there were 90.0 males.

The median income for a household in the city was $29,563, and the median income for a family was $38,114. Males had a median income of $27,778 versus $20,980 for females. The per capita income for the city was $17,711. About 9.9% of families and 15.9% of the population were below the poverty line, including 19.1% of those under age 18 and 7.9% of those age 65 or over.

Registered neighborhoods include University Heights, Bissett, Bradford Park, Doling, Grant Beach, Heart of the Westside, Midtown, Oak Grove, Parkcrest, Phelps Grove, Robberson, Rountree, Tom Watkins, Weller, West Central, Westside Community Betterment, and Woodland Heights.

Affiliated neighborhood groups unregistered with the city include: