Objective To investigate the alleviating effects of six citrus flavonoids-hesperidin， naringin， quercetin， kaempferol， nobiletin， and tangeretin on the neurotoxicity induced by co-exposure of profenofos and etoxazole， and to further explore the underlying neuroprotective mechanism of the most effective citrus flavonoid.Methods Using the wild-type N2 strain of Caenorhabditis elegans as an in vivo experimental model， the body length inhibition rate， movement frequency， predation rate， and chemotaxis index were selected as indicators to comprehensively assess the protective effects of six typical citrus flavonoids on the synergistic neurotoxicity induced by the co-exposure of profenofos and etoxazole. The protective effects of the most effective citrus flavonoid was elucidated by assessing changes in neurotransmitter levels， intracellular calcium ion （Ca²⁺） concentration， oxidative stress indicators， and gene expression levels.Results Hesperidin， naringin， nobiletin and tangeretin significantly alleviated the synergistic neurotoxicity induced by combined exposure to profenofos and etoxazole. Notably， hesperidin showed the highest efficacy in both developmental and behavioral evaluations. Mechanistically， hesperidin treatment elevated the contents of 5-hydroxytryptamine and dopamine in profenofos and etoxazole-exposed nematodes to normal levels， and significantly increased the intracellular Ca²⁺ concentration， while showing no significant effects on reactive oxygen species levels or the catalase activity. For gene expression， hesperidin intervention restored the levels of ser-7， lin-45， ctl-3， gst-4， kin-1， sca-1， daf-2， and jnk-1. Furthermore， it upregulated the gene expression of sod-3 and dop-2， and downregulated age-1.Conclusion Hesperidin can significantly alleviate the synergistic neurotoxicity induced by profenofos and etoxazole， primarily by modulating neurotransmitter levels， maintaining calcium ion homeostasis， and regulating oxidative stress-related pathways. This study provides new insights into potential strategies to mitigate the neurotoxicity induced by combined pesticide residues in food.