Depression is a common mental disorder. Previous studies have found that Schisandra chinensis lignans (SCL) exhibit significant therapeutic effects on depression, though its antidepressant mechanisms remain incompletely understood. This study aims to elucidate the molecular mechanisms by which SCL exerts neuroprotective and antidepressant effects, based on SCL's modern pharmacological neuroprotective properties and the physiological function of cannabinoid type 1 receptor (CB1R) in neuronal protection. By establishing a chronic unpredictable mild stress (CUMS)-induced depression model and administering CB1R antagonist AM251 to CUMS-treated animals, we conducted pharmacobehavioral experiments to evaluate SCL's ability to improve depression-like behaviors in mice. Additionally, we employed Western blot, hematoxylin-eosin staining, immunohistochemistry, immunofluorescence, and molecular docking to investigate SCL's antidepressant mechanism through CB1R-mediated regulation of brain-derived neurotrophic factor (BDNF). The use of animals in this study was approved by the Ethics Committee of Shenyang Pharmaceutical University, with the approval number: SYPU-IACUC-C2021-11-3-115. Pharmacobehavioral results demonstrated that SCL alleviates depression-like behaviors in CUMS model mice. Hematoxylin-eosin staining revealed that SCL improves neuronal pathological damage and neuroplasticity impairment caused by CUMS in the model. Western blot analysis revealed that SCL upregulates BDNF and CB1R expression, activates the proBDNF-tPA-BDNF pathway to promote proBDNF cleavage, and exerts anti-apoptotic effects. It also activates BDNF-TrkB-MEK-ERK-PKA-CREB and PI3K-AKT pathways to reduce neuronal damage and exert antidepressant effects. Further experiments confirmed that AM251 antagonized SCL's antidepressant effects by inhibiting its depression-like behavior and modulation of BDNF-related pathways. Specifically, SCL activates proBDNF-tPA-BDNF via CB1R to enhance BDNF production and anti-apoptotic effects, while simultaneously activating the downstream classical pathway BDNF-TrkB-ERK-PI3K-AKT to protect neurons and exert antidepressant effects. Molecular docking revealed the binding sites of six major components in SCL for CB1R. The study revealed that SCL exerts antidepressant effects by regulating BDNF through CB1R to alleviate neuronal damage.