BACKGROUND: Reflux esophagitis (RE) is a common disease which is caused by the reflux of stomach and duodenal contents. As a classic prescription of traditional Chinese medicine, Chaihu-Shugan-San (CSS) has been used in the treatment of RE. However, no critically designed overview to evaluate the systematic review of CSS for RE has been carried out. The purpose of this study is to evaluate the efficacy and safety of CSS in the treatment of RE. METHODS AND ANALYSIS: We will search the following sources without restrictions for date, language, or publication status: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) Cochrane Library, EMBASE, MEDLINE, China National Knowledge Infrastructure (CNKI), Wan Fang Database, Chinese Bio-medicine Database, and VIP Chinese Periodical Database. Study selection, data extraction, and assessment of the risk of bias will be performed by 2 reviewers independently. Revman software (v.5.3) will be used to perform the meta-analyses. RESULTS: This study will provide a comprehensive evaluation of the efficacy and safety of CSS for patients with RE. CONCLUSION: The findings will be an available reference to evaluate the efficacy and safety of CSS on RE and provide decision-making reference on which method to choose for clinicians. TRIAL REGISTRATION NUMBER: 10.17605/OSF.IO/5398R.