Abstract： Objective:To study the effects and mechanism of action of hyperbaric oxygen（HBO）therapy at different pressures on lipopolysaccharide（LPS）-induced cognitive dysfunction in mice.Methods:A total of 50 C57BL/6J healthy male mice were randomly divided into control group，model group，0.10 MPa group，0.15 MPa group，and 0.25 MPa group，with 10 mice in each group. After the chronic neuritis mouse model being established by intraperitoneal injection of LPS at a concentration of 500 μg/kg，the mice in the 0.10 MPa group were given oxygen at atmospheric pressure，the mice in the 0.15 MPa group and the 0.25 MPa group were given HBO therpy at 0.15 MPa and 0.25 MPa，repectively. The mice in the control group received intraperitoneal injection of saline. The mice of the control group and the model group were place in the HBO chamber without pressurization or oxygenation. Morris water maze test was used to evaluate mice’s behavioral changes. HE staining was performed to observe the morphological changes of neurons in the cerebral cortex and hippocampus，and Nissl staining was used to observe the morphology of Nissl bodies.Results:Compared with the control group，the model group showed a decrease in the number of platform crossings in the Morris water maze test（ P<0.05），disordered and irregular trajectories，disorganized and loose brain tissue structure in the cortex and hippocampus，fewer Nissl bodies，and larger gaps in HE staining. Compared with the model group，the 0.15 MPa and 0.25 MPa groups showed increases in the number of platform crossings（ P<0.05），more tightly and orderly arranged and more intact neurons in brain tissue with clearer layers，and darker staining of Nissl bodies. No significant difference was found between 0.25 MPa and 0.15 MPa groups in behavioral experiments，HE staining，and Nissl staining（ P>0.05）. Conclusion:HBO has a protective effect on the learning and memory abilities of the mouse model of cognitive dysfunction-related neuroinflammation induced by LPS. The mechanism of action may be related to HBO alleviating the damages of neurons in the mice cerebral cortex and hippocampus.