The highway passes through rural farming country and several small towns along its course through the Lower Peninsula.

I-196 functionally replaced M-21 between Holland and Grand Rapids with a portion retained under state maintenance as Old M-21, now M-121.

M-21 runs long the north back of the Grand, turning southeasterly and east to Lowell.

M-21 runs east of town through the southern end of the Lowell State Gaming Area and crosses into Ionia County.

It turns northeasterly through lightly forested farmland passing Bertha Brock Park as it approaches the city of Ionia.

The highway bypasses the village to the south and crosses into Clinton County near the eastern edge of town.

Western Clinton County's landscape is dominated by farms, interrupted by the community of Fowler.

The highway enters the county seat, St. Johns on State Street, passing through a residential section of town.

The trunkline follows Main Street into downtown and crosses the Shiawassee River between junctions with M-52 and M-71 in Owosso.

The remainder of the county is the same, dominated by farmland along a straight stretch of flat highway.

The landscape starts to transition to residential subdivisions as the roadway approaches the Flint area.

[3][4] The road crosses a former branch line of the Canadian National Railway (converted into a bicycle trail) east of the interchange.

[5] Corunna Road angles to the northeast near Bradley Avenue and terminates at Court Street.

The trunkline turns east and follows Court over a tributary of the Flint River near Aldrich Park.

Eastbound traffic follows 5th Street past the city and county buildings in the area.

MDOT reported that the peak AADT was 36,053 vehicles daily near the I-75 interchange in the Flint area.

[8] Before the Interstate era, M-21 extended across the entire Lower Peninsula, from the junction with US 31 in Holland near Lake Michigan east to the St. Clair River at Port Huron, and crossed into Canada where the Blue Water Bridge is currently located.

[11] The 1926 creation of the United States Highway System led to the extension of M-21 along US 16 to Grand Rapids.

[13][14] All in-city portions of M-21 were transferred to state control in 1931 with the passage of the Dykstra Act of 1931 (PA 131 of 1931).

[22][23] The first freeway segment of M-21 on the east end was built from Wadhams to Port Huron in 1966.

At the time, M-21 was extended along Fulton Street to the East Beltline, and the business loop was truncated into a spur route redesignated BS I-196.

It started at an intersection between M-21 (Court Street) and US 10 (Dort Highway) and ran southward concurrently with US 10 to Lapeer Road.

It continued to an intersection with M-15 south of Davison, where it turned northward, running concurrently with M-15 into downtown.

[19] During World War II, the state was building a beltline system for Grand Rapids.

From there, the highway ran along industrial areas on the north side of Wyoming, running parallel to the I-196 freeway.

M-21 turned northward along Grandville Avenue and entered the city of Grand Rapids.

M-21 continued eastward along Franklin Street before turning northward on Eastern Avenue into downtown Grand Rapids.

M-56 was a state trunkline highway from 1971 to the mid-1980s that replaced the M-21 designation from M-13 to Flint when the M-21 (now I-69) freeway was being built.

After the change, it turned south along M-13 on the Shiawassee–Genesee county line to the M-78 freeway and then routed eastward to replace M-78.