Objective To explore the relationship between expression of brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the hippocampus and forebrain cortex and depression induced by chronic stress in mice. Methods We randomly divided 58 SPF KM mice (29 male, 29 female) into a control group and observation group. We induced stress in the mice in the observation group via fasting, electric shock, and other techniques. The mice in the control group were not exposed to experimental stressors. We weighed the mice before stress induction, 10 days after, and 20 days after stress induction. We then observed and recorded the result of the Morris water maze test and open field test in both groups. We measured BDNF and VEGF expression in the hippocampus and forebrain cortex in each group, and analyzed the correlation. Results Before stress induction, there were no significant differences between the two groups (P> 0. 05). After stress induction, the mice in the observation group weighed significantly less than those in the control group ( P< 0. 01). The escape latency, swimming distance, and time spent in the second quadrant were significantly higher in the observation group vs. the control group (P< 0. 05 or P< 0. 01), but there were no significant differences in the time spent in the other quadrants ( P> 0. 05). The modification times and vertical movement scores of the mice in the observation group were significantly lower than those in the control group, and the retention time in the central area was significantly higher than that in the control group ( P< 0. 01). There was no significant difference in the number of defecation particles (P> 0. 05). The BDNF and VEGF expression levels in the CA1 area of the hippocampus and forebrain cortex were lower in the observation group vs. control group, but this difference was not significant (P> 0. 05). Conclusions Chronic stress can induce depressive behavior in mice, which may be related to decreased BDNF and VEGF expression in the hippocampus and forebrain cortex.