Route 80 is a state highway in southeastern Missouri.

The route is located in northern New Madrid and central Mississippi Counties.

Route 80's western terminus is at U.S. Route 61/62 near Matthews, which is located midway between Sikeston and New Madrid, with a junction with I-55 located about a mile (1.6 km) to the east.

Its eastern terminus is a dead end at the Mississippi River in Belmont.

At Belmont, there used to be a ferry connecting Route 80 to Kentucky Route 80, which is a major east–west thoroughfare across southern Kentucky, continuing into Virginia, as Virginia State Route 80.