U.S. Route 65 (US 65) is a north–south U.S. highway that runs from Clayton, Louisiana to Albert Lea, Minnesota.

Also in Springfield, the highway has junctions with U.S. Route 60 (also known as James River Freeway) and Interstate 44 (I-44).

From Buffalo to Preston, entering Hickory County, U.S. 65 remains a two-lane highway and has a four-way intersection with U.S. Route 54.

Continuing north, after passing through several towns, U.S. 65 then shares a concurrency with Route 7 before entering Warsaw, where the highway crosses over the western end of the Lake of the Ozarks and again becomes a four-lane highway at the intersection where it separates from Route 7.

At Sedalia (where it is called Limit Avenue), it has an intersection with U.S. Route 50 (known locally as Broadway Blvd).

At Marshall Junction, north of Sedalia in Saline County, U.S. 65 intersects with both Interstate 70 and U.S. Route 40.

In Marshall (where it is called Lexington, Ave), U.S. 65 returns to two-lanes and stays so all the way up to Iowa.