Route 52 is an east/west highway running from its eastern terminus at Route 133 7 miles (11 km) east of St. Elizabeth to the Kansas state line where it continues as K-52 (this road continues for 23 additional miles).

Highway 52 comprises 173 miles (278 km) of primarily two-lane roadway in Missouri.

A portion through Versailles and Eldon has a center lane for left turning.

It leaves Route 5 and then passes through Marvin, Barnett, and Eldon before crossing US 54.

It passes through Tuscumbia then it crosses the Osage River with a concurrency with Route 17.