The Laurentian Great Lakes have been subject to substantial modification from diverse anthropogenic stressors, including nutrient enrichment, climate change, chemical and biological pollutants, and invasive species, yet little is known of the relative historical influence of these factors. Here we analyze diverse fossil metrics from vibracores at two sites, a bay area (Anchor Bay) and a tributary (Clinton River) in the Lake St. Clair ecosystem to determine the ecological responses from land-use practices and invasive mussel invasions. Sediment cores spanning over 100 years indicated that the expansion of non-native Dreissena polymorpha and Dreissena rostriformis (dreissenid mussels) into Anchor Bay site after the mid-1990s was associated with ~ 60 to 95% reduction in algal and cyanobacterial abundances and twofold increase in sedimentary organic matter (SOM) and bioavailable phosphorus. These increases in SOM and bioavailable phosphorus are relatively similar to increases inferred from the late nineteenth century when large portions of the watershed were cleared and drained for agriculture. In contrast, the Clinton River site experienced a continuous increase in the influx of nutrients, organic matter, and elevated sedimentary phototrophic pigments during the twentieth century and into the twenty-first century. Site comparisons suggest different mechanisms inducing changes in primary production varied, where Anchor Bay was mainly affected by the comparatively recent (since ca. mid-1990s) endogenous influence of invasive species, while the Clinton River site was primarily influenced by the input of exogenous anthropogenic nutrients over the past 100 years. These new findings illustrate that watershed management and policies within large lakes with multi-jurisdictional (national) Area of Concerns should consider site-specific regulatory mechanisms.