Zebra mussels (Dreissena polymorpha) are an invasive species known to detrimentally affect native unionid mussels, a highly imperiled group of organisms. Yet, no study has compared the impact of infestation (direct attachment to unionid mussel shells) and presence of zebra mussels on glycogen storage under controlled conditions, nor examined the impact of zebra mussels at the southern edge of their North American distribution. Hence, the objectives of this study were to (1) examine the impact of infestation versus presence of zebra mussels with experiments in the laboratory and (2) collect data on glycogen concentrations of unionid mussels at field sites with and without zebra mussels. In the experiment, tissue samples were collected after 30 days from treatment tanks where (1) Threeridge (Amblema plicata) were artificially infested with zebra mussels, (2) zebra mussels were present with similar biomass, but shells of A. plicata were not infested, and (3) control tanks where zebra mussels were absent. Results from the experiments showed zebra mussel presence and infestation reduced glycogen by 38% and 66%, respectively. Results from the field were consistent with these findings. Variation in glycogen concentrations of mussels collected in the field was best explained by chlorophyll-a concentrations (coarse measure of food resource) and zebra mussel densities. Zebra mussels showed similar detrimental effects as in other studies despite their lower densities, which could be due to the additional metabolic costs associated with higher water temperatures. Our study suggests that the combined impact of invasive species and rising temperatures due to global warming needs to be considered for conservation and management plans.