ETHNOPHARMACOLOGICAL RELEVANCE: Jiao Sanxian, a customary term for the three Traditional Chinese Medicines of charred hawthorn (Crataegi Fructus), charred malt (Hordei Fructus Germinatus) and Liu Shenqu (Massa Medicata Fermentata), is a classic prescription for the treatment of functional dyspepsia (FD). This prescription is called "Jiao Sanxian" in China because people believe that it is a miracle medicine for enhancing digestion and improving stagnation of digestive system. Even though Jiao Sanxian is widely used in clinical treatment, the underlying mechanism has not been clarified to date. AIM OF THE STUDY: The present study is aimed to explore the efficacy and mechanism of Jiao Sanxian in improving the symptoms of FD in rats by using multiple pharmacological methods. MATERIALS AND METHODS: The Sprague Dawley (SD) rats were divided into control, model, Jiao Sanxian decoction low-dosage (JSXD LD), Jiao Sanxian decoction medium-dosage (JSXD MD), and Jiao Sanxian decoction high-dosage (JSXD HD) group at random. A FD model was established with reserpine, and animals were given intragastric administration. During this period, weight and food intake of animals were recorded. Samples of rat gastric antrum, spleen, and duodenum were collected for pathological staining and immunohistochemical determination of Ghrelin protein expression after 19 days of treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of related brain gut peptides in serum. Moreover, 16S rRNA sequencing was used to valuate the influence of intestinal flora structure of the cecal contents of experimental rats. And plasma metabolomics by Ultra Performance Liquid Chromatography coupled with Quadrupole-Time-of-Flight mass spectrometry (UPLC-Q/TOF-MS) were performed to further reveal the mechanism of action. RESULTS: Jiao Sanxian decoction (JSXD) group with different dosage could increase body weight and food intake, improve histopathological changes, and alter disordered brain gut peptides in FD rats. 16S rRNA sequencing results described that JSXD improved the disorder of structural composition, biodiversity and function of gut microbiota in FD rats. Metabolomics illustrated 26 metabolites with JSXD treatment underwent continuous changes, which revealed JSXD might exert digestive effect by ameliorating abnormal metabolic pathways. The most relevant metabolic pathways were arachidonic acid metabolism, pyruvate metabolism, glycerophospholipid metabolism, alanine, aspartate and glutamate metabolism. CONCLUSIONS: JSXD can improve functional dyspepsia in rats and the mechanism is related to regulate secretion of brain gut peptides, significantly improve the disorder of intestinal flora and ameliorated multi-metabolic pathways.