Objective: To systematically explore the pharmacokinetic distribution characteristics of the natural coumarin compound Auraptene in mice, as well as its improving effects and molecular mechanism on depression-like behavior induced by chronic unpredictable mild stress (CUMS). Methods: Male C57BL/6N mice were intraperitoneally administered Auraptene (AUR). Plasma and brain samples were subsequently collected at predetermined time points. High-performance liquid chromatography (HPLC) was used to evaluate its blood-brain barrier (BBB) penetration. Mice were randomly divided into control (CON) group, model (CUMS) group, AUR (15 mg/kg) group, and fluoxetine (Flx, 20 mg/kg) group, with drug intervention administered simultaneously after 4 weeks of CUMS modeling. Depressive- and anxiety-like behaviors were assessed using the sucrose preference test, open field test, three-chamber social interaction test, and tail suspension test. The expression levels of brain-derived neurotrophic factor (BDNF) in hippocampal tissues were detected by immunofluorescence and Western blot, and the contents of pro-inflammatory factors (IFN-γ, TNF-α) in hippocampal tissues were also measured. Results: Pharmacokinetic analysis showed that AUR was rapidly absorbed following intraperitoneal (i.p.) administration. The peak concentrations (Cmax) in plasma and brain tissue were observed at 30 and 45 minutes post-administration, respectively (Cmax of 1,845±127 ng/mL and 520±97.8 ng/g, respectively). Its plasma elimination half-life (t1/2) was approximately 199 min. The plasma exposure (AUC 0-240 min) over the observation period was 309,720.0 ng·min·mL?1, and the brain-to-plasma partition coefficient (Kp) was about 9.7%, indicating that AUR effectively penetrates the BBB. Behavioral assessments demonstrated that AUR intervention improved sucrose preference (P<0.001), reduced immobility time in the tail suspension test (P<0.001), and alleviated anxiety-like behaviors and social dysfunction (P<0.001). Molecular and biochemical analyses revealed that AUR not only attenuated the CUMS-induced abnormal increase in hippocampal pro-inflammatory factors (e.g., IFN-γ) (P<0.01), but also effectively reversed the CUMS-mediated downregulation of BDNF protein expression, particularly in the DG region (P<0.01). The comprehensive regulatory effect of AUR was comparable to that of the positive control drug, fluoxetine. Conclusion: Auraptene exhibits favorable blood-brain barrier permeability and can effectively ameliorate CUMS-induced depression, anxiety, and social withdrawal. The antidepressant mechanism of AUR may be closely associated with its actions in inhibiting neuroinflammatory responses, maintaining the neurotrophic system, and upregulating BDNF expression in the hippocampus.