Objective To explore the effects of venlafaxine on anxiety and depression-like behavior in rats withchronic restraint stress. Methods Thirty-six SD rats were randomly divided into control, model, and venlafaxine groups,with 12 rats in each group. The model and venlafaxine groups were given chronic restraint stress for 21 days, and wererestrained for 6 hours at the same time every day. Venlafaxine was administered intragastrically (6. 75 mg/ kg), and thecontrol and model groups were given distilled water intragastrically. Rats were tested for anxiety using the elevated plus mazeand scene fear test. Depression behavior was tested using the open field and forced swimming tests. Hematoxylin and eosin(HE) staining was used for the pathological examination of the rat hippocampus. A high performance liquidchromatography-electrochemical method was used to measure the content of 5-HT, NE and DA in the hippocampus, andplasma HPA axis CRH, ACTH and CORT levels were detected by ELISA. Results Anxiety and depression-like behaviorsin the model group were significant ( P <0. 01). Pathological changes such as neuron loss, disordered arrangement, andvacuolization of some cells were observed in the hippocampus of model rats. The contents of 5-HT, NE and DA weresignificantly downregulated ( P <0. 05), and plasma CRH, ACTH, and CORT levels were significantly increased in themodel group ( P <0. 01). Compared with the model group, after treatment with venlafaxine, anxiety and depression weresignificantly relieved ( P < 0. 05), hippocampal neuron injury was alleviated, the contents of 5-HT, NE and DA wereincreased to different degrees ( P < 0. 05), and plasma CRH, ACTH, and CORT levels were decreased ( P < 0. 05).Conclusions Venlafaxine significantly improve anxiety and depression-like behaviors in rats with chronic restraint stress,and alleviate hippocampal neuronal damage, which might be related to the upregulation of monoamine neurotransmitters in the brain and inhibiting excessive HPA axis stimulation in vivo.