The aim of the current study was to investigate whether metformin could counteract sevoflurane-induced neurotoxicity. In vitro experiments on the sevoflurane-induced nerve injury were performed using hippocampal neurons. Neuronal apoptosis was detected by an MTT assay. Protein expression levels of apoptosis-associated genes, including cleaved-caspase-3, apoptosis regulator BAX and apoptosis regulator Bcl-2 were detected by western blot analysis. The mechanism of the effect of metformin on sevoflurane-induced neuronal apoptosis was investigated using a sphingosine 1-phosphate receptor 1 (S1P1) antagonist (VPC23019) and mitogen-activated protein kinase kinase inhibitor (U0126). The current study revealed that metformin may reduce sevoflurane-induced neuronal apoptosis via activating mitogen-activated protein kinase (ERK)1/2 phosphorylation. VPC23019 and U0126 eliminated the neuroprotective effects of metformin on neuronal apoptosis, which suggests that metformin is able to protect against sevoflurane-induced neurotoxicity via activation of the S1P1-dependent ERK1/2 signaling pathway.