Abstract: Objective To investigate the clinical efficacy of vonoprazan fumarate combined with omeprazole sodium in the treatment of recurrent reflux esophagitis. Methods A total of 100 patients with recurrent reflux esophagitis admitted to the First Hospital of Qinhuangdao from January 2022 to January 2023 were enrolled. They were randomly divided into a monotherapy group (n = 50, receiving omeprazole sodium) and a combination group (n = 50, receiving vonoprazan fumarate combined with omeprazole sodium) using a random number table. The clinical outcomes were compared between the two groups. Results After 8 weeks of treatment, the combination group showed superior clinical efficacy compared to the monotherapy group. Levels of motilin, gastrin, and prostaglandin E2 were significantly higher (P＜0.05), while levels of interleukin (IL)-17 and IL-23 were significantly lower in the combination group (P＜0.05). Furthermore, the frequencies of liquid reflux, gas reflux, non-acid reflux, and acid reflux were significantly reduced in the combination group (P＜0.05). There was no statistically significant difference in the incidence of adverse reactions between the two groups during treatment (P ＞0.05). The recurrence rate within the one-year follow-up period was significantly lower in the combination group than in the monotherapy group (P＜0.05). Conclusion The combination therapy of vonoprazan fumarate and omeprazole sodium is significantly effective in treating recurrent reflux esophagitis. It effectively improves the levels of gastrointestinal hormones and inflammatory factors, reduces the frequency of esophageal reflux episodes, and demonstrates a favorable safety profile with a lower recurrence rate.