The river rises in the Northern Lower Peninsula, and flows in a generally southwesterly direction to its mouth at Lake Michigan at the eponymous city of Manistee.

Historically, the upper river was renowned for its outstanding Arctic grayling fishery, among the finest in the world and at the extreme southern limit of the range of this salmonid.

During this period huge numbers of white pine logs, some as large as 6 feet (1.8 m) in diameter, were floated down the river to the port at Manistee and eventually on to the lumber markets of Grand Rapids, Milwaukee and Chicago.

These deep glacial sands provide it with a remarkably stable flow of clean cold water year round, making it a popular river for fishing as well as canoeing.

[7] Native fluvial fish species in the Manistee River include brook trout (Salvelinus fontinalis) and the now extinct Arctic grayling (Thymallus arcticus).

Abiotic habitat conditions such as temperature, gravel, and water quality were found suitable for re-introduction of grayling, once the dominant salmonid in the State of Michigan.