The gut‑brain interaction is associated with impaired duodenal mucosal integrity and low‑grade inflammation, which have been proven to be important pathological mechanisms of functional dyspepsia (FD). Sini San (SNS) is a classical Chinese medicine used to treat FD, but its underlying mechanisms are poorly understood. The aim of the present study was to evaluate the effects of SNS on duodenal mucosal barrier injury and low‑grade inflammation with FD, and to assess its potential molecular mechanisms on the brain‑gut axis. FD rats were established using the iodoacetamide and tail‑squeezed methods. The expression of corticotropin‑releasing factor (CRF), CRF receptor 1 (CRF‑R1) and CRF‑R2, were determined by western blot analysis and/or immunohistochemistry (IHC). In addition, mast cell (MC) migration was assessed by IHC with an anti‑tryptase antibody, and histamine concentration was quantified using ELISA. The mRNA expression levels of tryptase and protease‑activated receptor 2 (PAR‑2) were quantified using reverse transcription‑quantitative PCR, and the protein expression levels of zona occludens protein 1 (ZO‑1), junctional adhesion molecule 1 (JAM‑1), β‑catenin and E‑cadherin were determined via western blot analysis. It was demonstrated that the expression level of CRF was downregulated in the central nervous system and duodenum following SNS treatment, and that SNS modulated the expression of both CRF‑R1 and CRF‑R2. In addition, SNS suppressed MC infiltration and the activity of the tryptase/PAR‑2 pathway in the duodenum. Furthermore, treatment with SNS restored the normal expression levels of ZO‑1, JAM‑1 and β‑catenin in FD rats. These findings suggested that the therapeutic effects of SNS on FD were achieved by restoring mucosal barrier integrity and suppressing low‑grade inflammation in the duodenum, which was at least partially mediated via the CRF signaling pathway.