The railway continued its extension westward until, in 1883, it linked with its eastward counterpart, completing the Sunset Route from Los Angeles to New Orleans. Today, the route of the BBB&C (now owned by the Union Pacific Railroad) is still an important and heavily operated railroad line.

In 1890, two real estate investors from Houston (R.M. Cash and L.E. Luckle) purchased four square miles of land directly on the route of the BBB&C, only a mile and a half from its first stop at Stafford's Point. They advertised the property as "a land of genial sunshine and eternal summer" in St. Louis, Missouri and its surrounding areas. Three years later, W.R. McElroy purchased eighty acres in the same vicinity, and in effort to promote the area jointly with Cash and Luckle in St. Louis, he named it "Missouri City". Its first actual settlers were from Arlington, Texas near Dallas and Fort Worth.

The settlement was officially registered in Texas in 1894, and began to take shape as a railroad town along US-90A at Texas Parkway, then known as Main Street, Blue Ridge Road, or Farm to Market Road 2234. Its growth took a challenging turn when, on Valentine's Day in 1895, shortly after the first group of settlers had arrived, the town was hit with a blizzard. This discouraged some of the newcomers who gave up and moved elsewhere. Those unwaivered stayed and found success in farming and ranching. Among its first businesses were a blacksmith shop, a depot, and a general store, which also housed the first post office. The first Catholic church was built in 1913, but was destroyed by a hurricane in 1915. The new church built to replace it stood until 1990.

Oil was discovered in nearby Blue Ridge in 1919; soon after, a salt mine opened there. Missouri City became the railroad shipping point for these two resources. In 1925, at the same location, natural gas was discovered. After a pipeline had been constructed the following year, Missouri City became the first town in Fort Bend County to make use of natural gas. With the benefit of a railroad, Missouri City had already been home to commuters who, by train, commuted to adjacent towns like Stafford's Point and Sugar Land to work. With the increase of automobiles and improvement of roads and highways in the early part of the 20th century, the developing community gradually attracted a wealth of newcomers. This gave birth to a new generation of commuters replacing railroad commuters that eventually became obsolete. By the 1950s, the town began to take shape as a notable "bedroom community" suburb of Houston.

After fear and rumor spread of possible annexation of the unincorporated town by Houston, town leaders scrambled to piece together a city government. On March 13, 1956, the community that began as a small settlement more than 55 years earlier was incorporated.

Missouri City has since seen tremendous economic growth, moving eastward, southward, and then westward. The city was first made over by Fondren Park (in Harris County), near US-90A, in the early 60s, followed by Quail Valley, along Cartwright Road between Texas Parkway and Murphy Road, in the late 60s. It should be noted that, unlike neighboring Houston, Missouri City has been a zoned city since 1981. Multifamily complexes (e.g. apartments and condominiums) are a rare find because of the current zoning ordinance.

In the 1970s, an influx of middle-class African Americans - most of them first-time homeowners - were attracted to developing communities south and west of Houston. Many of them made the subdivisions of Missouri City home. This influx occurred after an economic downturn caused property values and interest rates to drop. Teal Run and other unincorporated areas east of Highway 6 became ethnically diverse before neighborhoods farther west. Movement by black families has been characterized by neighborhood hopping, whereby families who can afford to move go to majority white neighborhoods, ostensibly to escape possible negative influences to their children. As a result of the influx, some white families moved to different communities and neighborhoods in a response known as 'white flight'. (White Flight usually further decreases property values, whereby a neighborhood is no longer seen as desirable to a significant segment of the population, and therefore worth less. Low income families tend to fill the void left by whites, and the process starts over again when minority members of the community once again seek a better neighborhood to live in.) Many of the newcomers were employees within nearby Houston work centers (e.g., Texas Medical Center, Greenway Plaza). A lot of Middle Class African Americans call Missouri City home. In 2000, it was named a model city for Middle-class African Americans by Black Entertainment Television (BET).

The Missouri City area's recent residential developments include the upscale, master-planned community of Lake Olympia, adjacent to Quail Valley in the Missouri City corporate limits, and the nearby unincorporated area of Sienna Plantation, situated south of State Highway 6, on and around land once occupied by plantations where, among other things, sugarcane and cotton were harvested.

Demographics
As of the census of 2000, there were 52,913 people, 17,069 households, and 14,645 families residing in the city. The population density was 1,781.7 people per square mile (687.9/km²). There were 17,481 housing units at an average density of 588.6/sq mi (227.3/km²). The racial makeup of the city was 44.29% White, 38.35% African American, 0.20% Native American, 10.60% Asian, 0.04% Pacific Islander, 4.46% from other races, and 2.06% from two or more races. Hispanic or Latino of any race were 10.88% of the population.

There were 17,069 households out of which 48.6% had children under the age of 18 living with them, 70.2% were married couples living together, 12.5% had a female householder with no husband present, and 14.2% were non-families. 11.9% of all households were made up of individuals and 2.4% had someone living alone who was 65 years of age or older. The average household size was 3.09 and the average family size was 3.36.

In the city the population was spread out with 30.8% under the age of 18, 7.0% from 18 to 24, 31.0% from 25 to 44, 25.7% from 45 to 64, and 5.4% who were 65 years of age or older. The median age was 36 years. For every 100 females there were 94.0 males. For every 100 females age 18 and over, there were 89.9 males.

According to a 2006 estimate, the median income for a household in the city was $79,132, and the median income for a family was $85,138. Males had a median income of $51,013 versus $36,786 for females. The per capita income for the city was $27,210. About 2.4% of families and 3.3% of the population were below the poverty line, including 3.5% of those under age 18 and 4.2% of those age 65 or over.

Economy
At the time of the 2000 census, the per capita income in Missouri City was $27,210, compared with $21,587 nationally. Two zip codes - 77459 and 77489 coexist, where the 77489 zip code extends into a section of the City of Houston east of Fondren Road with the eastern terminus at Chimney Rock Road. Fondren Road is the current demarcation between Missouri City and Houston - since the late 1970s, communities east of Fondren Road and north of FM 2234 - including Willowridge High School - have been part of the City of Houston since late 1979. Some residents refer to this "disputed" section - a nine-square mile section of Fort Bend County as Missouri City because of the 77489 zip code; in 1998, the City of Houston Super Neighborhood Council refers to this "disputed" section as the Fort Bend-Houston Super Neighborhood #41. Residents who reside east of Fondren Road and north of FM 2234 have considered this section of Fort Bend County as a stepchild community where (1) the City of Houston provides it services (public infrastructure, 911/emergency services, and garbage pickup), and (2) Fort Bend County services (county property taxes, courts, county government, sheriff, constable) take up the rest. There are nine voter precincts - it was in 2001 where Mayor Lee P. Brown won re-election for a final term.

Transportation
Missouri City is served by U.S. 90-A, Beltway 8 (Sam Houston Tollway) and FM 2234 (Texas parkway). Other nearby highways are U.S. 59, Highway 6 and Interstate 610. Although it does not have public transportation in the city limits itself, it is part of the service area of METRO. METRO operates the Missouri City Park and Ride located on Beltway 8 and Fondren Road and is served by express bus route 163 Fondren to Sharpstown and Downtown Houston and route 170 Missouri City Express to Texas Medical Center (where it terminates with a METRORail station there).