Esketamine (ES) has been shown to confer neuroprotection partly by exerting anti-inflammation, alleviating oxidative stress, enhancing neuronal vitality, and promoting synaptic remodeling. Nonetheless, its precise function in SAE and the associated mechanisms are not understood. In this study, we investigated the neuroprotective potential of ES at behavioral, structural, and functional levels in vivo and in vitro. C57BL/6J mice administered with lipopolysaccharide (LPS) served as the research model and were injected with 10 mg/kg ES intraperitoneally. Fiber photometry was performed to record Ca