The Upper Columbia River (UCR) received historical releases of smelter waste resulting in elevated metal concentrations in downstream sediments. Newly hatched white sturgeon hide within the rocky substrate at the sediment–water interface in the UCR for a few weeks before swim-up. Hiding behavior could expose them to metal contaminants, and metal toxicity could contribute to population declines in white sturgeon over the past 50 years. This study evaluates whether there is a link between the toxicity of dissolved metals across the sediment-water interface in the UCR and the survival of early life stage (ELS) white sturgeon. Toxicity of dissolved metal mixtures is evaluated using a combination of previously collected laboratory and field data and recently developed metal mixture toxicity models. The laboratory data consist of individual metal (Cd, Cu, Pb, and Zn) toxicity studies with ELS white sturgeon. The field data include the chemical composition of surface and pore water samples that were collected across the sediment–water interface in the UCR. These data are used in three metal accumulation and two response models. All models predict low toxicity in surface water, whereas effects concentrations greater than 20% are predicted for 60–72% of shallow pore water samples. The flux of dissolved metals, particularly Cu, from shallow pore water to surface water likely exposes prime ELS sturgeon habitat to toxic conditions.