Background Based on 122 cases reported in China, data mining indicated that Sini Powder (SNP) and the Zuojin Pill (ZJP) are both widely used as the basic recipe for treating Gastroesophageal Reflux Disease (GERD). Objectives To evaluate the intervention effects of Sini Zuojin Decoction (SNZJD) in patients with GERD. Methods A comprehensive collection of randomized controlled trials (RCTs) using SNZJD in patients with GERD that were published in domestic and foreign journals was made by computer retrieval. RevMan 5.3 software was used for meta-analysis and bias risk assessment, Stata 14.0 software was used for sensitivity analysis, GRADE profiler 3.6 was used to evaluate the level of evidence, and trial sequential analysis (TSA), employed to control for random errors, was performed to assess the main outcomes. Network pharmacology analysis was applied to preliminarily study the mechanisms of action of SNZJD on GERD. Results Thirteen articles were eventually included, covering a total of 966 patients. Meta-analysis indicated that: the SNZJD plus traditional stomach medicines (SPTSM) group was more effective than the traditional stomach medicines (TSM) group (RR = 1.16, 95% CI [1.04, 1.29], P = 0.009); the experimental group with SNZJD was significantly better than TSM controls in improving heartburn, substernal chest pain, acid regurgitation, and food regurgitation symptoms (P < 0.0001); SPTSM could significantly decrease total symptom scores with substantial effectiveness (P < 0.00001). The recurrence rate and adverse effects of SNZJD treatment were significantly reduced (P < 0.05). TSA showed that the effective rate of meta-analysis might be reliable, but the recurrence and safety results were still uncertain. According to the evaluation by the GRADE method, the quality of evidence was low. Besides, SNZJD might treat GERD by acting on related targets and pathways such as inflammation, hormone regulation, and so on. Conclusions SNZJD might be useful in the treatment of GERD, but its long-term effects and specific clinical mechanisms are unclear. Due to the poor quality of the evidence, more samples and high-quality clinical studies should be tested and verified in the future.