Chemicals used in sea lice management strategies in salmonid aquaculture include the avermectin class of compounds that can accumulate and persist in the sediments underneath salmon farms and directly impact nontarget benthic fauna. The effects of sediment organic carbon content and chemical residence time (CRT) on the lethal and sublethal toxicity of emamectin benzoate (EB; formulation: Slice®) and ivermectin (purified) and a combination of both were examined in two benthic invertebrates, the amphipod Eohaustorius estuarius and the polychaete Neanthes virens. In both species, increased sediment organic carbon content significantly reduced lethal toxicity, a modulation that was more pronounced for ivermectin and combination exposures. At a CRT of 4 months, lethal toxicity was reduced in E. estuarius but was unaffected in N. virens. Sublethal toxicity in N. virens (burrowing behavior) was modulated by sediment organic carbon and CRT in a similar manner to the trend in lethal toxicity. Inconsistencies in behavior (phototaxis) in E. estuarius made conclusions regarding toxicity modification by sediment organic carbon or CRT inconclusive. Our results indicate that environmental factors including sediment organic carbon content and the time compounds reside in sediments are important modifiers of chemotherapeutant toxicity in nontarget benthic species and should be considered when regulatory decisions regarding their use are made. Environ Toxicol Chem 2022;41:1918–1936. © 2022 SETAC