The original M-65 was created by 1919 on a discontinuous series of roads between the Ohio state line and Flint; the two sections were later joined together before the highway was replaced by US 23 in 1926.

The highway runs north along Hale Road through a mixed forest and agricultural area inland of the Saginaw Bay in Arenac County.

North of town, the highway crosses the main channel of the Au Gres River before it intersects M-55 in a rural area of Iosco County about 15 miles (24 km) west of Tawas City.

From there, the road continues due north through fields until reaching the edge of Huron National Forest in the northern part of the county.

North of the county line, the trunkline follows Baker and State roads near Vaughn and Hunters lakes.

[4][5] North of Glennie, the highway passes Clear Lake as it continues through rural Alcona County.

The two trunklines run concurrently curving to the northwest past the eastern terminus of county road F-32 into Curran.

[8] The section of M-65 concurrent with M-32 has been listed as a part of the National Highway System,[9] a network of roads important to the country's economy, defense, and mobility.

[12] When the United States Numbered Highway System was created on November 11, 1926, the original M-65 was redesignated as part of US 23.

[14][15] By 1936, the highway was lengthened northwards to end in Glennie; a second segment was also added that ran north from the Alcona–Alpena county line to Lachine.

[16] Around the end of the decade, US 23's routing was moved in another location to follow the lakeshore; this time the highway was rerouted between Alpena and Rogers City.

[20][21] By the next year, the northern end of the highway near Posen was moved to eliminate several zig-zagging segments of roadway from the routing; M-65 ran due north to terminate at US 23 after the change.

[23][24] The MSHD realigned M-65 from a series of zig-zagging roads to a single set of curves along the Alcona–Alpena county line in late 1961.

A second designation was added on September 22, 2005, when the Federal Highway Administration listed the roadway as the River Road National Scenic Byway.

[27] Beginning in 1999, MDOT spent substantial sums of money over a five-year program to upgrade M-65 and US 23 by refurbishing and replacing bridges and adding more passing lanes.