The health of bee populations worldwide is affected by multiple factors, of which neonicotinoids are considered to be a main reason. Although most neonicotinoids are highly toxic to bees, some of them are relatively safe. To explore the molecular mechanism of these differences in toxicity, homology modelling, molecular docking and molecular dynamics simulations were applied to study the interactions between Apis mellifera (α8)₂(β1)₃ nAChR and high bee-toxic neonicotinoid (imidacloprid, IMI), medium bee-toxic (thiacloprid, THI) and low bee-toxic butenolides (flupyradifurone, FPF). It was observed that three major interactions were similar across all systems, including water-bridge networks, π-π interactions and the polar interactions between the electron-withdrawing pharmacophores and the receptor. The calculated binding free energy was similar between IMI and THI. While FPF was the lowest bee-toxic, it displayed the strongest binding free energy value, the additional C–H⋯O H-bonds with Arg80 and Trp179 were the main reason. The bee toxicities of neonicotinoids and other nAChR modulators are not only determined by receptor affinities, but also by other factors (for example physicochemical properties and metabolic detoxification). All influencing factors should be fully considered in the future design of new eco-friendly insecticides that are safe for bees.