Objective To explore the clinical effect of Vonoprazan Fumarate Tablets combined with Mosapride Citrate for the treatment of patients with gastroesophageal reflux disease (GERD). Methods A total of 61 GERD patients were randomly divided into vonoprazan group (n=31) or lansoprazole group (n=30). Patients in the vonoprazan group received Vonoprazan Fumarate Tablets combined with Mosapride Citrate for treatment, whereas the lansoprazole group received lansoprazole combined with Mosapride Citrate for treatment. Both groups receive a 4⁃week treatment. The efficacy, safety, and pre⁃ and post⁃treatment gastrointestinal hormones and inflammatory factors levels were compared between the two groups. Results After treatment, the vonoprazan group exhibited a higher remission rate of syndromes as compared with the lansoprazole group (P<0.05). Both groups interpreted elevated levels of serum motilin and gastrin, whereas decreased levels of serum cholecystokinin (CCK), vasoactive intestinal peptide (VIP), interleukin (IL)⁃1β, IL⁃6, IL⁃8, and 5⁃hydroxytryptamine after treatment. The vonoprazan group depicted higher levels of serum motilin and gastrin, while lower levels of serum CCK, VIP, IL⁃1β, IL⁃6, IL⁃8, and 5⁃hydroxytryptamine after treatment as compared with the lansoprazole group (P<0.05). There was no statistically significant difference in the total incidence rate of adverse reactions of drugs between the two groups (P>0.05). Conclusion Vonoprazan Fumarate Tablets combined with Mosapride Citrate for the treatment of GERD exerts significant efficacy, which can prominently ameliorate patients' gastrointestinal hormones levels, and decrease inflammatory factors levels, exerting favorable safety.