The highway runs from South Haven to Webberville along an indirect path through both rural areas and larger cities.

The trunkline follows five overall segments: a southeasterly track from South Haven to Oshtemo Township (just west of Kalamazoo), a northerly path to Plainwell, a southeasterly route to Richland, a northeasterly course to the Hastings area and an easterly route through the Lansing area.

Several sections of the highway were realigned during its history, one of these changes led to the creation of a business loop in Grand Ledge.

In January 2019, the highway was rerouted north to bypass downtown Kalamazoo, where it had historically formed a high traffic trunkline through the city.

[4] After the concurrency ends, M-43 turns east and then back north to run between Little Long and Gull lakes.

The road continues on a general north-northeast track through rural areas and beside several lakes in Barry County before meeting M-179 and M-37.

Downtown, M-37 leaves town to the south, while M-43 heads north before curving around the east, passing through farm fields approaching the community of Woodland.

[2][3] In Lansing, the highway travels splits to follow the one-way streets of Saginaw (eastbound) and Oakland (westbound) near the Sparrow Specialty Hospital.

The trunkline then passes over US 127 just before the paired one-way streets merge back together on Grand River Avenue.

After the merge, M-43 heads southeast through East Lansing, passing the main campus of Michigan State University and Spartan Stadium.

[7] The second is between I-96/I-69 in Delta Township and the junction between Saginaw Street and Grand River Avenue in East Lansing.

[15][16] When M-43 was rerouted in 1954, the new course of the highway ran concurrently with M-66 for a few miles in rural northeastern Barry County.

[17][18] All of the highway was completely paved in 1956 when a new routing opened northeast of Hastings, bypassing Coats Grove.

[19][20] The fourth change in the Barry County routing was made by the next year; the highway was rerouted due northward out of Hastings along Broadway Street.

M-43 was extended from its eastern end in Lansing in 1962 along a section of highway that was formerly part of US 16 on Grand River Avenue; the extension to Webberville was made when the I-96 freeway opened that year.

The section not concurrent with M-100 was turned over to local control and removed from the state trunkline highway system.