We assessed a large-scale fish die off event resultant of prolonged anoxic conditions on Grand Lake St. Marys in west central Ohio, U.S., during the summer of 2020, and used this as the basis for comparing long-term species diversity in the lake over the past century. Fish collections were made along a series of shoreline and open water transects, totaling approximately 1.5% of the entire 5220 ha lake area (majority of surveys were shoreline), wherein we identified a total of 12,351 fish comprised of 25 taxa. We used this die off event, combined with recent near shore seine survey data, as an opportunity to assess the modern assemblage structure and to serve as a reference point to prior collected data over the past century. Combining these recent data with historical records, we found that although 57 species have been recorded from the lake dating back to the mid-1800s, only 30 taxa are known to inhabit the lake today. Some of the lost taxa predictably include more intolerant species from the Darter (Percidae), Minnow (Cyprinidae), and Sucker (Catostomidae) families; however, there were also instances of increases in taxa resulting from both state stocking efforts (e.g. Flathead Catfish, Pylodictis olivaris) and natural distribution expansions (e.g. Freshwater Drum, Aplodinotus grunniens). Overall, we attribute the changes to the fish assemblage as negative, given no intolerant taxa currently inhabit the lake. We attribute these long-term changes to watershed wide destruction of natural forest, wetland, and prairie habitats that once typified the region.