Abstract: Objective To explore the role of purinergic ion channel receptor 7(P2X7R) in the pathological mechanism of depression and provide novel theraputic targets for depression treatment. Methods A mouse model of depression was established through chronic social defeat stress (CSDS). Behavioral changes were assessed using the tail suspension test, forced swim test, sucrose preference test, and social interaction test. The levels of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) were detected by Western blot. The hippocampal neurogenesis was examined by immunofluorescence in each group of mice. Results Compared with the control group, mice in the CSDS group showed a significant increase in immobility time (P<0.01), while sucrose preference index, social interaction time, BDNF/TrkB protein levels, and the number of doublecortin (DCX)-positive cells remarkably decreased (P<0.01). Compared with the CSDS group, mice in the CSDS+A438079 group exhibited a significant decrease in immobility time (P<0.01), while sucrose preference index, social interaction time, BDNF/TrkB protein levels, and the number of DCX-positive cells remarkably increased (P<0.01). Conclusions The P2X7R antagonist (A438079) alleviates CSDS-induced depression-like behaviors in mice by activating the BDNF/TrkB signaling pathway. These findings provide new therapeutic targets for the prevention and treatment of depression.