Objective: To investigate the synergistic effect of rifaximin combined with rabeprazole in treating functional dyspepsia (FD) and analyze its mechanism. Methods: A total of 126 FD patients were enrolled and divided into an observation group and a control group (63 per group) according to different treatment methods. Patients in the control group received oral rabeprazole sodium enteric-coated tablets, while those in the observation group received additional rifaximin tablets. After 4 weeks of treatment, the two groups were compared in terms of therapeutic efficacy, gastrointestinal hormones, inflammatory factors, gut microbiota counts, and intestinal mucosal barrier markers. Results: After 4 weeks of treatment, the total effective rate in the observation group was higher than that in the control group (P<0.05), motilin levels were increased in both groups (P<0.05), and the observation group was higher than the control group (P<0.05), gastrin and somatostatin levels were decreased in both groups (P<0.05), and were lower in the observation group (P<0.05), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-α) levels were decreased in both groups (P<0.05), and were lower in the observation group (P<0.05). The counts of Enterococcus and Enterobacter were decreased in both groups (P<0.05), and were lower in the observation group (P<0.05), while the counts of Lactobacillus and Bifidobacterium were increased in both groups (P<0.05), and were higher in the observation group (P<0.05). Diamine oxidase (DAO) and D-lactate levels were decreased in both groups (P<0.05), and were lower in the observation group (P<0.05). Conclusion: The combination of rifaximin and rabeprazole shows a synergistic effect in treating FD, which may be related to improving gastrointestinal hormone levels, reducing inflammation, modulating gut microbiota, and repairing the mucosal barrier.