The osprey (Pandion haliaetus) is a well-known sentinel of environmental contamination, yet no studies have traced pharmaceuticals through the water–fish–osprey food web. A screening-level exposure assessment was used to evaluate the bioaccumulation potential of 113 pharmaceuticals and metabolites, and an artificial sweetener in this food web. Hypothetical concentrations in water reflecting “wastewater effluent dominated” or “dilution dominated” scenarios were combined with pH-specific bioconcentration factors (BCFs) to predict uptake in fish. Residues in fish and osprey food intake rate were used to calculate the daily intake (DI) of compounds by an adult female osprey. Fourteen pharmaceuticals and a drug metabolite with a BCF greater than 100 and a DI greater than 20 µg/kg were identified as being most likely to exceed the adult human therapeutic dose (HTD). These 15 compounds were also evaluated in a 40 day cumulative dose exposure scenario using first-order kinetics to account for uptake and elimination. Assuming comparable absorption to humans, the half-lives (t1/2) for an adult osprey to reach the HTD within 40 days were calculated. For 3 of these pharmaceuticals, the estimated t1/2 in ospreys was less than that for humans, and thus an osprey might theoretically reach or exceed the HTD in 3 to 7 days. To complement the exposure model, 24 compounds were quantified in water, fish plasma, and osprey nestling plasma from 7 potentially impaired locations in Chesapeake Bay. Of the 18 analytes detected in water, 8 were found in fish plasma, but only 1 in osprey plasma (the antihypertensive diltiazem). Compared to diltiazem detection rate and concentrations in water (10/12 detects, <method detection limits [MDL]–173 ng/L), there was a lower detection frequency in fish (31/233 detects, <MDL–2400 ng/L); however when present in fish, all values exceeded the maximum diltiazem concentration found in water. Diltiazem was found in all 69 osprey plasma samples (540–8630 ng/L), with 41% of these samples exceeding maximum concentrations found in fish. Diltiazem levels in fish and osprey plasma were below the human therapeutic plasma concentration (30 000 ng/L). Effect thresholds for diltiazem are unknown in ospreys at this time, and there is no evidence to suggest adverse effects. This screening-level exposure model can help identify those compounds that warrant further investigation in high-trophic level species.