Sevoflurane may exert neurotoxic effects on the developing brain. Coenzyme Q10 (CoQ10) has been reported to reduce sevoflurane anesthesia-induced cognitive deficiency in 6-day-old mice. However, its specific mechanisms remain unknown. Apolipoprotein E (ApoE) has been reported to lead to the initiation of neurodegeneration in patients with Alzheimer’s disease (AD) and may serve an important role in anesthesia-induced neurotoxicity. The present study aimed to reveal the role of ApoE in the pathogenesis of tau protein hyperphosphorylation and neuroinflammation enhancement caused by sevoflurane anesthesia, as well as the protective mechanism of CoQ10 in an anesthetic sevoflurane treatment model of primary mouse hippocampal neurons. For that purpose, the neurons were randomly assigned to the following groups: i) Control; ii) sevoflurane; iii) control+corn oil; iv) sevoflurane+corn oil; v) control+CoQ10; and vi) control+CoQ10. CoQ10 or corn oil alone was added to the medium on day 4 of neuron culture. The neurons in the sevoflurane group were treated with 21% O2, 5% CO2 and 4.1% sevoflurane for 4 h, whereas the control group only with 21% O2 and 5% CO2 on day 5. Samples were collected immediately after anesthesia or control treatment. ATP, superoxidase dismutase (SOD)1, ApoE mRNA, total ApoE, full-length ApoE, ApoE fragments, Tau5, Tau-PS202/PT205 (AT8), Tau-PSer396/404 (PHF1), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β levels were measured with ELISA, quantitative PCR, western blotting and immunocytochemistry. The results of the present study indicated that sevoflurane anesthesia significantly decreased the ATP and SOD levels, but increased ApoE mRNA, total ApoE protein, full-length ApoE, ApoE fragments, phosphorylated tau (AT8 and PHF1) and neuroinflammatory factor (TNF-α, IL-6 and IL-1β) expression levels compared with those in the control group. The use of CoQ10 reversed the expression of these factors. These results suggested that sevoflurane treatment damaged mouse hippocampal neurons, which may be associated with the expression of ApoE and its toxic fragments. CoQ10 improved energy replenishment and inhibited oxidative stress, which may lead to a decrease in ApoE and phosphorylated tau protein expression, thus mitigating the sevoflurane-induced neuroinflammation in mouse hippocampal neurons.