To observe the effects of propofol on blood-brain barrier (BBB) disruption in septic mice and explore its possible mechanisms. Methods: Thirty male SPF C56BL/6 mice were randomly divided into three groups (n=10): control group (Con), sepsis group (LPS), and propofol-treated group (PF). A sepsis mouse model was established in LPS and PF group mice through intraperitoneal injections of 10 mg/kg lipopolysaccharide (LPS). Immediately and 6 hours after modeling, the PF group mice were given intraperitoneal injections of 50 mg/kg propofol, and the LPS group mice were given equal volume injections of saline. Mice in the Con group were intraperitoneally injected with saline only. Twenty-four hours later, the behavioral changes of mice in the different groups were evaluated by neuroreflex scoring. Serum levels of NSE and S100β were measured by ELISA kits. The permeability of BBB and water content of brains were determined by Evans blue extravasation and the wet/dry ratio of brain tissue. The protein expression of Occludin, claudin-5, and MMP-9 were detected by Western blot to assess BBB integrity. Results: Compared with the Con group, the LPS group showed higher levels of serum NSE and S100β, water content and EB content in brain tissues, and MMP-9 protein expression and lower neuroreflex scores and decreased Occluding and Claudin-5 expression (P<0.05). Compared with that of the LPS group, the serum NSE and S100β levels, brain tissue water and EB content, and MMP-9 protein expression in the PF group were decreased, while the neuroreflex scores and Occluding and Claudin-5 expression were significantly increased (P<0.05). Conclusion: Propofol can alleviate BBB damage and decrease its permeability in septic mice, and the mechanism may involve the inhibition of MMP-9 expression.