The Port of Saint Louis is part of the Mississippi River System in the central United States. The Port of Saint Louis is about 318 nautical miles downriver on the Missouri (381 kilometers or 237 miles east direct) from the Port of Kansas City. The Port of Saint Louis is also about 335 nautical miles upstream (171 kilometers or 106 miles north direct) from the Port of Memphis, Tennessee. The Port of Saint Louis is on the west bank of the Mississippi, while East St. Louis, Illinois, lies across the river to the east. Since 1876, the Port of Saint Louis has been administratively independent from St. Louis County, Missouri. The 2010 US Census reported a population of over 319 thousand people in the city and more than 2.8 million in the metropolitan area.

The Port of Saint Louis is the second biggest inland port in the United States, and it is an important transportation and distribution hub for the Mid-West. The northernmost ice-free port on the Mississippi, the Port of Saint Louis handles cargoes that include grain, petroleum products, coal, and chemicals. The Port of Saint Louis is also an important center for rail and road transportation, and it has a large international airport. Headquarters for several leading corporations, the Port of Saint Louis economy relies on a major service sector that includes healthcare, banking and finance, airline administration, telecommunications, and education. Manufacturing is also important to the economy, and the Port of Saint Louis produces chemicals, beer, metal products, military aircraft and missiles, and automobiles. High-tech industries are also thriving in the Port of Saint Louis, and Scott Air Force Base is just to the east in Illinois.

The Mississippian culture built the earliest settlements in the area that would become the Port of Saint Louis. They built over 24 burial mounds that are within the city limits today. The earliest mounds have been dated to about 1050AD.

In the 14th Century, tribes like the Missouria and Osage, Siouan-speaking people, migrated into the Missouri Valley to escape pressure from French Canadian settlers coming into the Great Lakes region. The people established villages along the Missouri and Osage Rivers, resulting in conflicts with the Sauk and Fox tribes.

By the time Europeans arrived in the Port of Saint Louis area, the Tamaroa, a member tribe of the Illinwek (Illinois Confederacy), lived on both banks of the Mississippi where the Illinois and Missouri Rivers met. Tamaroa leaders were among the Illinwek who signed the 1818 Treaty of Edwardsville ceding land claims in Illinois and Missouri to the United States.

Another treaty in 1832 listed the Tamaroa with fellow Illinwek tribes, the Kaskaskia and the Peoria. After that treaty, Tamaroa descendants merged with the Peoria. Today, as a result of the forced removal of indigenous peoples from the Port of Saint Louis area, the Tamaroa live with the Confederated Peoria Tribe in Ottawa County, Oklahoma.

French explorers Louis Jolliet and Jacques Marquette passed through the area of the future Port of Saint Louis in 1763. The next year, New Orleans' Pierre Laclede Liguest founded a fur-trading post in the Spanish-controlled territory, bringing his consort and her children with him. In 1764, 14-year old Auguste Chouteau (one of Liaclede's "step-children") commanded a group of men who built a village on the west bank of the Mississippi. Laclede then named the village after French King Louis XIV and became one of the town's most powerful residents.

After the 1803 Louisiana Purchase, the Port of Saint Louis became part of the United States. It became the government center for the Louisiana Territory in 1805, and seat of the Missouri Territory in 1812.

When steamboats arrived in 1817, the Port of Saint Louis began to boom as a major river port. Throughout the 19th Century, immigrants from Germany and Ireland populated the growing city. When Missouri won statehood in 1821, the capital was temporarily moved to Saint Charles. In 1826, Jefferson City became the state capital.

The Port of Saint Louis was an important outfitting point for fur traders, explorers, and settlers moving farther west. In 1849, a deadly outbreak of cholera hit the city, and the Port of Saint Louis riverfront was destroyed when a steamboat exploded. During the American Civil War, the Port of Saint Louis was a base for Union troops, and it was under martial law.

In the 1850s, railroads came to the Port of Saint Louis. By the 1870s, railroads had all but replaced steamboats and the river as the major mode of transportation. While the fur trade had been important to the area's economy until the middle 19th Century, the Port of Saint Louis became an industrial center in the latter half of the century. Manufacturers produced iron, shoes, and clothing, and several breweries were located in the Port of Saint Louis. In 1874, the Eads Bridge allowed the railroads to cross the Mississippi, ensuring that the Port of Saint Louis would continue to be an important transportation hub.

In 1904, the St. Louis World's Fair (actually named the Louisiana Purchase Exposition) was held to the west of the Port of Saint Louis in Forest Park. With the Olympic Games being held in the city as well, the Port of Saint Louis came to international attention. Charles A. Lindbergh's world-famous 1927 flight across the Atlantic in the Spirit of St. Louis was financed by a group of Saint Louis businessmen, bringing more attention to the Port of Saint Louis.

In the late 19th and early 20th Centuries, the Port of Saint Louis continued to grow. While developed slowed during the Great Depression of the 1930s, World War II brought renewed growth. By 1950, over 850 thousand people lived in the Port of Saint Louis.

After the mid-20th Century, Port of Saint Louis population began to decline as residents of European ancestry moved to the suburbs. By 2000, the population had fallen by some 60%, back to the level it had been in 1880.

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