Objective To investigate the improvement effect of 18kD translocator protein (TSPO) ligand YL-IPA08 on lipopolysaccharide (LPS)-induced depressive, anxiety-like behaviors and cognitive dysfunction in mice and the related anti-inflammatory mechanism. Methods (1) 50 male C57BL/6J mice were randomly divided into control group, LPS model group, LPS+YL-IPA08 (1.0 or 3.0 mg/kg) group and YL-IPA08 (3.0 mg/kg) group, with 10 mice in each group. Mice in LPS model group were intraperitoneally injected with LPS (0.5 mg/kg) once on day 1 and day 8. Mice in LPS+YL-IPA08 (1 or 3 mg/kg) and YL-IPA08 (3.0 mg/kg) groups were intragastrically administered YL-IPA08 (1.0 or 3.0 mg/kg) for 13 consecutive days, once a day. From the 9th to 12th day, the open field test, tail suspension test, forced swimming test, novel object recognition test and elevated-plus maze test were used to evaluate the depressive, anxiety-like behaviors and cognitive function of mice. Western blotting was used to detect the expression levels of postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of mice. (2) BV2 mouse microglia cells were divided into control group (phosphate buffered saline incubation for 1 h), LPS model group (incubated with 1.0 mg/L LPS for 6 h), LPS+YL-IPA08 (0.5 or 1.0 μmol/L) group (incubated with 0.5 or 1.0 μmol/L YL-IPA08 for 1 h and then incubated with 1 mg/L LPS for 6 h), and YL-IPA08 group (incubated with 1.0 μmol/L YL-IPA08 for 1 h). ELISA was used to detect the expression levels of inflammatory factors interleukin-1β (IL-1β), interferon-γ (IFN-γ), IL-4, IL-10 and transforming growth factor-β₁ (TGF-β₁). Western blotting was used to detect the expression levels of the members of Smad protein family (Smad2, Smad3) mediating signal transduction of TGF-β. Results (1) The results of behavioral experiments showed that there was no significant difference in the total movement distance of mice in each group in the open field test (P>0.05). Compared with the control group, the number of entries and duration time in the central area of mice in LPS model group were significantly decreased (P<0.05); the immobility time in the tail suspension test and the forced swimming test was significantly prolonged (P<0.05); the recognition index in the novel object recognition test, the percentage of entries into the open arms and the percentage of duration time in the open arm in the elevated-plus maze test were significantly decreased (P<0.05), and the expression levels of PSD95 and BDNF in the prefrontal cortex were significantly decreased (P<0.05). Compared with LPS model group, above behavioral and expression changes in LPS+YL-IPA08 (3.0 mg/kg) group were significantly reversed (P<0.05). (2) Compared with control group, the expression levels of pro-inflammatory factors IL-1β and IFN‑γ in BV2 cells in LPS model group were significantly increased (P<0.05), and the expressions of anti-inflammatory factors IL-4, IL-10 and TGF-β₁ were significantly decreased (P<0.05), and the expression levels of Smad2 and Smad3 were significantly decreased (P<0.05). Compared with LPS model group, the expression level of IFN-γ in BV2 cells in LPS+YL-IPA08 (0.5 μmol/L) group was significantly decreased, and the expression levels of IL-4 and TGF-β₁ were significantly increased (P<0.05); the above changes were significantly reversed in LPS+YL-IPA08 (1.0 μmol/L) group (P<0.05). Conclusion YL-IPA08 can significantly attenuate LPS-induced depressive and anxiety-like behaviors in mice and alleviate the decline in cognitive dysfunction, which mechanism may be related to improving neuroinflammation and regulating the TGF-β/Smad pathway.