〔Abstract〕 Objective To explore the effect of esketamine on anxiety-depressive-like behavior in mice and its relationship with inflammation. Methods SPF grade healthy adult male C57BL/6J mice, weighing 20-24 g, were used in the exprement. The random number table method was used to divide into 5 groups(n=8): control group(Con group), esketamine group(ESK group), model group(LPS group), model+esketamine prevention group(LPS+ESK1 group) and model + esketamine treatment group(LPS+ESK2 group). An inflammation-induced anxiety-depression model was prepared by intraperitoneal injection of LPS 0.83 mg/kg. The ESK group was injected with esketamine 10 mg/kg; LPS group was injected with LPS 0.83 mg/kg; LPS+ESK1 group was injected with LPS 0.83 mg/kg before 24 hours intraperitoneal injection of esketamine 10 mg/kg; and the LPS+ESK2 group was injected with LPS 0.83 mg/kg and 30 minutes later with esketamine 10 mg/kg. 24 h after intraperitoneal injection of LPS, the anxiety-depression-like behaviors of mice were measured using behavioral experiments. At the end of behavioral experiments, the spleen was taken immediately; hippocampal tissues were taken and enzyme-linked immunosorbent assay(ELISA) was used to detect the contents of interleukin-1β(IL-1β), tumor necrosis factor alpha(TNF-α) and interleukin 6(IL-6) and neuronal pathological changes in hippocampal tissues were observed by HE staining. Results Compared with the Con group, mice in the LPS group showed increased anxiety and depression-like behavior(P<0.05), increased spleen weight/body weight(P<0.05), increased hippocampal tissue concentrations of IL-1β, TNF-α and IL-6(P<0.05), and increased neuronal degeneration necrosis, there was no statistically significant difference in these indicators in the ESK group compared with the Con group. Compared with the LPS group, mice in the LPS+ESK1 and LPS+ESK2 groups showed reduced anxiety-depression-like behavior(P<0.05), decreased splenic weight/body weight(P<0.05), hippocampal tissue IL-1β, TNF-α, IL-6 concentrations were reduced(P<0.05), and neuronal degeneration necrosis was reduced. Compared with the LPS+ESK1 group, the LPS+ESK2 group showed an increase in the distance travelled in the central area of the open field experiment and the distance into the open arm of the elevated cross maze experiment(P<0.05), a decrease in IL-6 and TNF-α concentrations(P<0.05), and a reduction in the degree of neuronal damage. Conclusion Esketamine ameliorates LPS-induced anxiety-depression-like behavior and neuronal damage in mice by a mechanism that may be related to reduced inflammation.