Objective To study the therapeutic effects of Yigan Fupi decoction (YGFP) on irritable bowel syndrome (IBS) and its mechanism of action in repairing the intestinal barrier and reducing IBS sensitivity through the PKA/ PKC-CREB pathway. Methods Baby rats separated from their mother were randomly divided into a model control (M) and a YGFP group, while baby rats without maternal separation were used as a normal control(N)group.The YGFP group was given YGFP for 4 weeks. Abdominal withdrawal reflux was used to evaluate intestinal sensitivity. Liquid chromatography tandem mass spectrometry and ELISA were used to detect bile acid metabolite concentrations and serum levels of interleukin ( IL)-6 and CXCL1, respectively. HE staining was used to observe pathological changes in the colon, and Western Blot and immunohistochemistry were used to analyze the relative protein expression levels of PKA, PKC, CREB, 5HT2AR, 5-HT7R, ZO-1, and Claudin 1. Results Compared with the normal control group, the M group showed a significantly decreased visceral pain threshold, significantly increased levels of total bile acid metabolites, IL-6, and CXCL1, significantly increased relative expression of PKA, PKC,CREB, 5HT2AR, and 5-HT7R, and significantly decreased relative expression of ZO-1 and Claudin 1. Compared with the M group, the YGFP group showed a significantly increased visceral pain threshold, significantly reduced levels of total bile acid metabolites, IL-6, and CXCL1, significantly reduced relative expression of PKA, PKC,CREB, 5HT2AR, and 5-HT7R, and increased relative expression of ZO-1 and Claudin 1. Conclusions YGFP effectively improved IBS through a mechanism that may involve repair of the intestinal barrier and reduced sensitivity through the PKA/ PKC-CREB pathway.