Lake Michigan’s drowned river mouths (DRM) are hydrologically unique systems with both riverine and large-lake influences. Serving as focal points for human development, DRMs have experienced a history of industrialization, urbanization, and are now moving towards an era of restoration and revitalization. The goal of this study was to examine water quality in 12 DRMs along Lake Michigan’s eastern shoreline. We hypothesized that there is a latitudinal gradient in indicators of water quality in these DRM lakes, which is the result of natural land cover, anthropogenic land use, and underlying geology. We identified a latitudinal gradient in land use/land cover with developed land area more abundant in southern DRMs and forest more abundant in northern land area; this distinction was evident at both the local and whole watershed geographic scales but was more distinct at the local scale. Water quality followed suit with specific conductance, chlorophyll-a, and total phosphorus (TP) concentrations higher in southern DRMs and lower in northern DRMs; whereas, Secchi disk depth showed the opposite trend. Multivariate analysis results were consistent with the relationship of water quality and latitudinal gradient. Thermal stratification and low dissolved oxygen (DO) concentrations in the hypolimnion were more common in deeper (i.e., greater than 4 m) areas of DRMs; low DO in the hypolimnion was more likely in southern DRMs than in northern DRMs. These results provide a foundation for future research initiatives in helping separate anthropogenic vs. natural stress in these systems, which provide critical ecosystem services for their surrounding communities.