This study examined metal levels (especially U and Ni) in the tail tissues of water snakes from contaminated (Tim’s Branch) and reference areas on the Department of Energy’s Savannah River Site (SRS). Home ranges of snakes were quantified to determine the ratio of the habitat that they use in relation to the contaminated areas to better estimate exposure Compared to conventional methods that do not. The exposure assessment indicated that water snakes in the contaminated areas could expect U exposure at 3–4 orders of magnitude greater than the Agency for Toxic Substances and Disease Registry’sMinimum Risk Level (MRL) from ingestion of amphibians and fish. Ni and U, in addition to Se, Mn, and Cu, were related to increased DNA double-strand breakage (DDSB) in water snakes.We report burdens for each metal individually, but the results of the DDSB indicated that these metals did not behave independently, but as a suite. If we did not have a secondary endpoint (DDSB), we might have assumed from the exposure predictions and tissue burden analyses that U was the sole metal of concern to water snakes in Tim’s Branch. These data also imply that these toxicants do not biomagnify at the spatial and temporal scale of this study.