U.S. Route 36 in Missouri runs from the Pony Express Bridge over the Missouri River in St. Joseph to the Mark Twain Memorial Bridge over the Mississippi River in Hannibal. After leaving the Missouri River valley, U.S. 36 then links major cities in Northern Missouri with Kansas City and cities in the east. From Cameron to the Illinois state line, it is overlapped with Route 110, also known as the Chicago–Kansas City Expressway. Starting in St. Joseph, it passes through the cities of Cameron, Hamilton, Chillicothe, Macon, Shelbina, Monroe City, and Brookfield. The final 2 miles (3.2 km) of US 36 in Missouri is concurrent with I-72. The route passes through mostly flat, fertile, productive farmland. Even though there are some surface intersections, U.S. 36 has many grade-separated interchanges and town bypasses that suggest a future extension of I-72 west from Hannibal.

US 36 across Missouri parallels the route of the Hannibal and St. Joseph Railroad, which was the reason St. Joseph was selected for the Pony Express. The two towns were the second and third largest cities in the State of Missouri prior to the American Civil War. Prior to the establishment of the railroad in the late 1850s, the stagecoach route was called the "Hound Dog Trail."^[3]

The road was originally Route 8 from 1922 to 1926, before being designated as US 36. Over the years some busier sections were widened to four lanes. On August 3, 2005, residents of Macon, Marion, Monroe, Shelby, and Ralls counties approved Proposition 36B, which excluded Ralls County from the Transportation Development District, and allowed for a 4-lane US 36 to be constructed without Ralls County's participation. On July 10, 2010, work was completed and the route ceremonially opened making US 36 a four-lane highway across the entire state, saving considerable travel time.^[4]

Presently, I-72 ends at US 61 (Avenue of the Saints) in Hannibal and was planned to extend westward to St. Joseph along US 36, but the proposal was shelved for years. In the interim, further lengthening was proposed by Marion County who published a five-item transportation list that was finalized by the County Commission on February 16, 2016, adding US 36, from the Mark Twain Memorial Bridge across the Mississippi River to the split of US 24 and US 36 near Rocket Plaza, as a new priority. Citing potential benefits including economic development and marketing of Hannibal Lakeside Industrial Park, the Commission advocate extending I-72 west approximately seven miles (11 km).^[5] In May 2023, the extension plans of I-72 to St. Joseph were renewed under the belief it would relieve traffic off of I-70.^[6] However, in July 2023, a bill to run a $2.5 million study was vetoed by Governor Mike Parson who said that it was not the right time to run the study.^[7]

All exits are unnumbered.