The effects of multi-walled carbon nanotube addition to sediment on the toxicity of diphenhydramine were investigated using invertebrate and fish models. Sediment elutriate exposures were undertaken with the freshwater crustacean Ceriodaphnia dubia to compare the toxic effects of diphenhydramine in the presence and absence of sediment and multi-walled carbon nanotubes. In both sediment and solution-only treatments, addition of 0.318 mg/g of functionalized multi-walled carbon nanotubes significantly decreased overall 48-hour mortality relative to the positive control. In a subsequent study, juvenile fathead minnows (P. promelas) were exposed to sublethal concentrations of diphenhydramine in the presence of natural sediment, with some treatments receiving MWCNTs. Addition of MWCNTs did not have a protective effect upon DPH-related growth inhibition, and did not reduce the whole-body burden of DPH in exposed fish. Mass-balance calculations indicated that significant amounts of DPH were adsorbed to MWCNTs, and DPH concentrations in water and sediment were commensurately reduced.