Objective: Depression imposes a huge health problem in the world. Recent studies report that berberine has neuroprotective effects. This study was investigated to evaluate the effects of berberine on depression and the potential underlying mechanisms. Methods: This experimental study included 48 mice, 8 CD1 mice and 40 C57 mice. Experiments were performed in the Laboratory Animal Center of China Three Gorges University, between May 2016 and February 2017. Chronic social defeat stress (CSDS) was used to build the depressive-like behaviors model. Three behavior tests, quantitative polymerase chain reaction, and Western blot were used to assay the changes in vivo. Results: We found that, in mice model induced by CSDS, berberine treatment increased mobility times in forced swim test and tail suspension test and reduced corticosterone level in serum. Furthermore, berberine increased traveled distance, frequencies in enter the central square, and duration time on the center square in the open field test as well. Further experiments showed that berberine treatment upregulated neuronal PAS domain protein 4 (NPAS4) and brain-derived neurotrophic factor (BDNF) protein/mRNA expressions in hippocampus tissue of CSDS mice. Conclusion: The present results suggested that berberine possessed properties in antidepressive-like behaviors, which might be partly attributed to upregulation of NPAS4 and BDNF expressions in hippocampus.