To observe the effect of propofol pretreatment on the depression-like behavior and hippocampal inflammatory response of lipopolysaccharide (LPS)-induced sepsis in mice and to explore its possible mechanism. Methods: Sixty healthy ICR mice were randomly devided into six groups (n=10): control group (group C), propofol group (group P1), LPS group (group L5), and propofol + LPS groups (groups L5P1, L5P2, and L5P5). Sepsis was induced in mice by injection with 5 mg/kg LPS. Group P1 was injected with 10 mg/kg propofol. Group L5P1, group L5P2, and group L5P5 were injected with 10 mg/kg, 20 mg/kg, and 50 mg/kg propofol, respectively. After 30 minutes, mice were injected with 5 mg/kg LPS. Group C was injected with the same amount of normal saline. All injections were intraperitoneal. After 24 hours, the depression-like behavior of mice was tested by the sucrose preference test, tail suspension test, and forced swimming test. Mice were sacrificed after behavior tests; subsequently, the expression level of inflammatory factors TLR4, P65 (main protein in NF-κ B), and MD-2 were detected by Western blot. Results: Compared with group C, group L5 showed decreased sucrose intake, increased tail suspension time, and inceased expression of TLR4, P65, and MD-2 (P<0.05). Compared with group L5, group L5P1 showed increased sucrose intake and reduced expression of TLR4, P65, and MD-2 (P<0.05); group L5P2 showed decreased sucrose intake, decreased tail suspension time, and reduced expression of P65 and MD-2 (P<0.05); group L5P5 showed increased sucrose intake and reduced expression of P65 (P<0.05). Conclusion: Propofol can improve the depression-like behavior and reduce the expression of hippocampal inflammatory factors in LPS-induced sepsis in mice. The mechanism may be related to inhibiting the TLR4/MD-2 pathway and reducing inflammatory responses.