Delayed toxicity is a phenomenon observed for aquatic invertebrates exposed to nicotinic acetylcholine receptor (nAChR) agonists such as neonicotinoids. Furthermore, recent studies observed an incomplete elimination of neonicotinoids from exposed amphipods. However, a mechanistic link between receptor binding and toxicokinetic modeling has not been demonstrated yet. The elimination of the neonicotinoid thiacloprid in the freshwater amphipod Gammarus pulex was studied in several toxicokinetic exposure experiments, complemented with in vitro and in vivo receptor binding assays. Based on the results, a two-compartment model was developed to predict uptake and elimination kinetics of thiacloprid in G. pulex. An incomplete elimination of thiacloprid independent of elimination phase duration, exposure concentrations and pulses was observed. Additionally, the receptor binding assays indicated irreversible binding of thiacloprid to the nAChRs. Accordingly, a toxicokinetic-receptor model consisting of a structure and a membrane protein (i.e., nAChR) compartment was developed. The model successfully predicted internal thiacloprid concentrations across various experiments. Our results help understanding the delayed toxic and receptor-mediated effects towards arthropods caused by neonicotinoids. Furthermore, the results suggest that more awareness towards long-term toxic effects of irreversible receptor binding is needed in a regulatory context. The developed model supports future toxicokinetic assessment of receptor binding contaminants.