The Manistique River's drainage was one of the last zones in Michigan to be clear cut, with old-growth timber being felled as late as the 1910s.

[4][5] Sediments at the site contained high levels of polychlorinated biphenyls (PCBs) and heavy metals resulting from historical pollution by sawmills, a paper mill, and small industries along the river.

[4][6] A 1996 remedial action plan for the AOC identified five "beneficial use impairments" caused by the pollution: Three of these impairments have been removed from the designation (degradation of benthos in 2006, loss of fish and wildlife habitat in 2008, and beach closings in 2009) following remediation projects,[4] which have included placement of temporary caps over contaminated areas and dredging of contaminated sediment, beginning in the 1990s.

[8] Lampreys historically were prevented from swimming upstream of the lowermost portion of the river by a dam in the city of Manistique, built in 1919.

Fish and Wildlife Service and other agencies have developed plans to install a sea lamprey barrier at the site.