Background Postoperative cognitive dysfunction (POCD) is a neurodegenerative disorder with impairment of cognition. Sevoflurane anesthesia has been found to lead to CD and microRNAs (miRNAs) were reported to affect cognitive function. This study investigates the neuroprotective effect against sevoflurane anesthesia-induced CD. Methods HE staining was used to detect the pathological change of hippocampal neuron. Morris water maze test was used to analyze latency time, platform crossing and swimming speed. Quantitative real-time PCR (qRT-PCR) and western blotting were performed to examine the mRNA and protein expression of miR-410-3p, IL-6, TNF-alpha, IL-1 beta and C-X-C motif chemokine receptor 5 (CXCR5). Dual-luciferase reporter assay was used to detect the relationship between miR-410-3p and CXCR5. Results MiR-410-3p was downregulated in sevoflurane anesthesia-induced rats and cells and act as a suppressor in sevoflurane anesthesia-induced hippocampal neuron apoptosis and inflammation. Furthermore, miR-410-3p was identified to bind with CXCR5. Further analysis showed that CXCR5 expression was increased by sevoflurane treatment, whereas was repressed by miR-410-3p overexpression. Moreover, miR-410-3p could inhibit sevoflurane anesthesia-induced hippocampal neuron apoptosis by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Conclusion These data indicated that miR-410-3p exhibited its neuroprotective effect on sevoflurane anesthesia-induced CD by targeting CXCR5 via PI3K/Akt signaling pathway. Our study may potentially provide a new light on the pathogenesis and therapeutic method for sevoflurane anesthesia-induced CD.