Minocycline has been implicated in the treatment for multiple diseases in the nervous system for its neuroprotective properties. However, the mechanism by which minocycline benefits postoperative anesthesia-induced cognitive dysfunction is still unclear. In this study, we introduced minocycline to a rat model of anesthetic-induced learning and memory impairment, to investigate the effects of minocycline on neuroinflammation, beta amyloid (Aβ) deposition, and activation of nuclear factor κB (NF-κB) signaling pathway in the hippocampus. Aged rats were treated with sevoflurane to induce cognitive impairment with and without pre-administration of minocycline. The rats were then subjected to Morris water maze tests to evaluate their learning and memory performance. Subsequently, apoptosis in the hippocampal tissue was assessed with TUNEL assays. Furthermore, the levels of apoptosis-related proteins and pro-inflammatory cytokines, Aβ responses, and activation of the NF-κB signaling pathway in the hippocampus were examined by Western blot analysis. Our results revealed that minocycline effectively alleviated sevoflurane-induced cognitive impairment in aged rats. Minocycline reduced sevoflurane-induced neuronal apoptosis and inflammation, as well as suppressed sevoflurane-induced Aβ accumulation and activation of NF-κB signaling pathway in the hippocampus of aged rats. In conclusion, our findings indicate that minocycline is a potent agent to counteract sevoflurane-induced cognitive impairment and neurotoxicity in the nervous system of aged rats, which is likely to be mediated via NF-κB signaling pathway.