Sevoflurane is a common anesthetic agent used in surgical settings and previous studies have indicated that it exerts a neurotoxic effect. However, the molecular mechanism underlying this side effect is unknown. In addition, the human microRNA-302 (hsa-miR-302) family members have been reported to be involved in neuronal cell development and biology. Thus, the present study aimed to investigate the potential implication of hsa-miR-302e in the sevoflurane-induced cytotoxicity on human hippocampal cells (HN-h). HN-h cells were transfected with hsa-miR-302e mimic, hsa-miR-302e inhibitor or negative controls and subsequently exposed to different concentrations of sevoflurane. An MTT assay was used to assess the cytotoxicity of sevoflurane on HN-h cells. Cell apoptosis was determined by flow cytometry. The levels of lactate dehydrogenase release, reactive oxygen species, lipid peroxidation and intracellular calcium (Ca2+) were additionally detected. Reverse transcription-quantitative polymerase chain reaction and western blotting were conducted to determine mRNA and protein expression, respectively. A luciferase assay was performed for validating the targeting of OXR1 by hsa-miR-302e. The results indicated that sevoflurane induced a decrease in cell viability, malondialdehyde and reactive oxygen species production, lactate dehydrogenase release, intracellular Ca2+ production, calcium/calmodulin-dependent protein kinase II phosphorylation and apoptosis. In addition, treatment with sevoflurane induced the expression of hsa-miR-302e while the expression of its target, oxidation resistance gene 1 (OXR1), was significantly downregulated. Inhibition of hsa-miR-302e expression protected neuronal cells from sevoflurane cytotoxicity. Mechanistic studies demonstrated that OXR1 was a direct target of hsa-miR-302e. Furthermore, the overexpression of OXR1 abolished the effect of sevoflurane on neuronal cells. The results of the present study indicated that sevoflurane exerts its neurotoxic effect by regulating the hsa-miR-302e/OXR1 axis. Therefore, the manipulation of the hsa-miR-302e/OXR1 pathway will be useful for preventing sevoflurane-induced neurotoxicity.