Objective To investigate the clinical effect of Chaihu Shugan Powder combined with proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux disease (GERD). Methods A total of 212 patients with GERD were enrolled and divided into erosive esophagitis (EE) group and non-erosive reflux disease (NERD) group, with 106 patients in each group, and all patients met the diagnostic criteria for liver-stomach heat accumulation in traditional Chinese medicine. Both groups were further randomly divided into treatment group and control group, with 53 patients in each group. The patients in the two treatment groups were given Chaihu Shugan Powder combined with PPIs, and those in the two control groups were given PPIs alone. The course of treatment was 8 weeks for all groups. The reflux diagnostic questionnaire (RDQ) was used after treatment to evaluate the improvements in symptoms and attack frequency, and the patients were followed up at 4 weeks after treatment to observe recurrence. Results Of all patients, 198(93.4%) completed the study. All groups had a significant reduction in RDQ score after the 8-week treatment (P<0.05), followed by an increase in RDQ score after 4 weeks of drug withdrawal (P<0.05), which remained lower than the score before treatment (P<0.05). For the patients with EE or NERD, the treatment group had a significantly lower RDQ score than the control group after the 8-week treatment and after 4 weeks of drug withdrawal (P<0.05). Conclusion Chaihu Shugan Powder combined with PPIs can improve the symptoms of patients with GERD with liver-stomach heat accumulation and has a better clinical effect than PPIs alone, and it can also reduce recurrence after drug withdrawal.