In ancient China, bee venom was widely used to treat various diseases.Although using bee venomis not currently a mainstream medical method, some have applied it to treat certain conditions,includingidiopathic facial paralysis(IFP). Recently, melittin(Mel), the main active component of bee venom, has been shown strong anti-inflammatory and analgesic effects. However, how bee venom improves neurological dysfunction in facial paralysis remainsunknown. This study aimed to investigate the anti-neurotraumatic effect of Mel on Schwann cells(SCs), the main cells of the neuron sheath, injured by oxidative stress. A model of hypoxicSCswas established,and CCK-8 assay, siRNA transfection, enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, western blot, immunofluorescence, and cell ultrastructure analyses were conducted to investigate the mitigation of hypoxia-induced damage to SCs in vitro, revealing the effects of Melon oxidative stress injury in SCs. The overexpression of HIF-1αin CoCl2-induced SCs (p < 0.05) indicated the establishment of an SCs hypoxia model. The proliferation and regeneration process of the hypoxic SCsenhanced in the Mel-treated group compared to the CoCl2group has been proventhrough the CCK-8 experiment (p < 0.0001) and S-100 mRNA expression detection (p < 0.0001). Theincreased level of reactive oxygen species (ROS) (p < 0.001) and decreased superoxide dismutase (SOD) levels (p < 0.05) in the CoCl2-induced SCs indicatedthat Mel can alleviate the oxidative stress damage to SCs induced by CoCl2. Mel alleviated oxidative stress and inflammation in hypoxic SCs by reducing pro-inflammatory cytokines IL-1β (p < 0.0001) and TNF-α (p < 0.0001). In addition, Mel augmented cellular vitality and regulated indicators related to oxygen metabolism, cell repair, neurometabolism, and vascular endothelial formation after hypoxia, such as C-JUN (p < 0.05), glial cell line-derived neurotrophic factor (GDNF; p < 0.001), vascular endothelial growth factor(VEGF; p < 0.05), hypoxia-inducible factor 1-alpha (HIF-1α; p < 0.05), interleukin-1 receptor type 1 (IL-1R1; p < 0.05), enolase1(ENO1; p < 0.05), aldose reductase(AR; p < 0.01), SOD (p < 0.05), nerve growth factor(NGF; p < 0.05), and inducible nitric oxide synthase(iNOS; p < 0.05). In terms of its mechanism, Mel inhibited the expression of proteins associated with the NF-κB pathway such as IKK (p < 0.01), p65 (p < 0.05), p60 (p < 0.001), IRAK1 (p < 0.05), and increased IKB-α (p < 0.0001). Moreover, knocking out of IL-1R1 in the si-IL-1R1 group enhanced the therapeutic effect of Mel compared to the Mel-treated group (all of which p < 0.05). This research provided evidence of the substantial involvement of IL-1R1 in oxidative stress damage caused by hypoxia in SCsand proved that Mel alleviated oxidative stress injury in SCs by targeting IL-1R1 to downregulate the NF-κB-mediated inflammatory response. Mel could potentially serve as an innovative therapeutic approach for the treatment of IFP.