Several organic contaminants (OCs) have been detected in bald eagle (Haliaeetus leucocephalus) nestling (eaglet) plasma in the upper Midwestern United States. Despite frequent and relatively high concentrations of OCs in eaglets, little is understood about potential biological effects associated with exposure. We screened an existing database of OC concentrations in eaglet plasma collected from the Midwestern United States against bioactivity information from the ToxCast database. ToxCast bioactivity information consists of concentrations expected to elicit responses across a range of biological space (e.g. cellular, developmental, etc.) obtained from a series of high throughput assays. We calculated exposure-activity ratios (EAR) by calculating the ratio of plasma concentrations to concentrations available in ToxCast. Bioactivity data were not available for all detected OCs. Therefore, our analysis provides estimates of potential bioactivity for 19 of the detected OCs in eaglet plasma. Perfluorooctanesulfonic acid (PFOS) EAR values were consistently the highest among all study areas. Maximum EAR values were ≥1 for PFOS, perfluorononanoic acid, and bisphenol A in 99.7, 0.53 and 0.26% of samples, indicating that some plasma concentrations were greater than what may be expected to elicit biological responses. About 125 gene targets, indicative of specific biological pathways, were identified as potentially being affected. Inhibition of several CYP genes, involved in xenobiotic metabolism, were most consistently identified. Other identified biological responses have potential implications for motor coordination, cardiac functions, behavior, and blood circulation. However, it is unclear what these results mean for bald eagles, given that ToxCast data are generated using mammalian-based endpoints. Despite uncertainties and limitations, this method of screening environmental data can be useful for informing future monitoring or research focused on understanding the occurrence and effects of OCs in bald eagles and other similarly-positioned trophic species.