In 1930, the first segment of the current routing of M-65 was designated.

Between 1938 and 1941, this segment was also designated as part of a rerouted U.S. Route 22.

Other segments of the modern routing were designated M-92 and M-47 at the time.

The northernmost segment was designated in 1973, and was most recently paved in 1990.

This segment of the highway is concurrently designated Tennessee State Route 86.

This segment was designated as LA 3114 and was opened to traffic in January 1969.

This segment was originally designated as a portion of US 50.

The entire eastern segment was designated as old WIS 69 in 1918.

As a logical extension of the nomenclature described above, this segment is sometimes designated as S3.

Currently, the following segments are designated as part of the National Expressway route: