Objective To investigate the alleviating effects of six citrus flavonoids, hesperidin (Hsp), naringin (Nar), quercetin (Que), kaempferol (Kap), nobiletin (Nob), and tangeretin (Tag), on the neurotoxicity induced by co-exposure of profenofos (PFF) and etoxazole (ETO), and to further explore mechanisms of the citrus flavonoid with the best intervention effect. 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 PFF and ETO. The citrus flavonoid with the best intervention effect was screened out, and its intervention mechanisms were explored from the perspectives of neurotransmitter levels, intracellular calcium ion (Ca2+) concentration, oxidative stress indicators, and gene expression level. Results Hsp, Nar, Nob, and Tag (10 μM) showed good alleviating effects on the synergistic neurotoxicity induced by co-exposure of PFF and ETO. Among them, Hsp showed the optimal intervention effect in developmental and behavioral evaluations. Mechanistic studies demonstrated that Hsp treatment can elevate the contents of 5-hydroxytryptamine (5-HT) and dopamine (DA) in PFF+ETO-exposed nematodes to normal levels, significantly increase the intracellular Ca2+concentration, but exerted no significant influence on reactive oxygen species (ROS) levels or the catalase (CAT) activity. Furthermore, Hsp intervention normalized the expression of genes including ser-7, lin-45, ctl-3, gst-4, kin-1, sca-1, daf-2, and jnk-1, upregulated sod-3 and dop-2 expressions, and downregulated age-1 expression. Conclusion: Hsp can significantly alleviate the synergistic neurotoxicity induced by PFF and ETO, primarily modulating neurotransmitter levels, maintaining calcium ion homeostasis, and regulating oxidative stress-related pathways. This study provides new insights into the potential interventions for neurotoxicity caused by combined pesticide residues in food.