Post-stroke depression (PSD) refers to a series of affective disorder syndromes that occur after stroke and are often accompanied by physical symptoms. PSD presents with low mood and lack of interest as the main characteristics along with the symptoms of stroke. The physical symptoms of PSD include sleep disorder, loss of appetite, and reluctance to communicate. Although Wendan decoction has been suggested to be effective in the treatment of PSD, there is no meta-analysis providing evidence for the usefulness of Wendan decoction for treating PSD.The following electronic databases will be searched: the Cochrane Library, PubMed, EMBASE, China National Knowledge Infrastructure, Wan Fang databases, Chinese Biomedical Literature Database, and China Science and Technology Journal Database. Each database will be searched from its inception to November 2021. Two independent researchers will conduct study selection, data extraction, and risk bias assessment. Any discrepancies will be resolved through consultation with a third researcher. If the included data are suitable, we will conduct a meta-analysis using RevMan v5.4 software.In this systematic review, the effectiveness and safety of Wendan decoction in the treatment of PSD will be evaluated.The findings of this meta-analysis will provide evidence-based data for the application of Wendan decoction in the treatment of PSD.Individual patient data and privacy will not be involved in this research,so ethics approval is not required.INPLASY2021110018.Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.