Major depressive disorder (MDD) is a highly prevalent debilitating psychiatric disease and a serious public health problem worldwide. Brain structural MRI and postmortem studies on patients with depression have revealed changes in the anatomy and functionality in various brain regions, including the amygdala, thalamus, hippocampus, and prefrontal cortex (PFC). The alterations in these brain regions could be a result, in part, of the dysregulation of the neurotrophic factors. Neuregulin1 (NRG1) is one of the neurotrophic factors, and our previous study showed that the NRG1-ErbB4 signaling pathway plays a critical role in epilepsy. In this study, we established a chronic social defeat stress (CSDS) model to investigate the role of the NRG1-ErbB4 signaling pathway in depression-like behaviors. In CSDS mice, we found that the NRG1 protein expression levels were significantly decreased both in the medial prefrontal cortex (mPFC) and hippocampus, while phosphorylated ErbB4 only decreased in the mPFC. In addition, lateral ventricle NRG1 administration significantly rescued depression-like behaviors in the susceptible group. The current study suggests that the NRG1-ErbB4 signaling pathway may exert a protective role in MDD.