Abstract: Patients with diarrhea-predominant irritable bowel syndrome generally have the pathological characteristics of intestinal mechanical barrier injury. To explore the repair effect of pogostone on intestinal mechanical barrier damage and its mechanism, a cell barrier damage model was first established using Caco-2 cells. After treatment with different final mass concentrations of pogostone, the cell survival rate was detected by MTT assay, the monolayer permeability of cells was verified by detecting the concentration change of fluorescein isothiocyanate-dextran (FITC-dextran, 4kDa), and the expression of occludin and ZO-1 proteins was detected by immunofluorescent technique and Western blotting. The effects of pogostone on cell barrier function and key proteins were systematically studied. Second, the CB-Dock2 online docking website was used for simulation calculation to study the binding energy between pogostone and the occludin and ZO-1 proteins. Furthermore, a rat model of diarrhea-predominant irritable bowel syndrome was constructed (set as the IBS-D model control group and high-, medium-, and low-dose pogostone groups), and rats maintained under conventional feeding conditions for 3 days were set as the blank control group. The overall changes of condition in rats in each group after treatment with different doses of pogostone were studied. The abdominal wall withdrawal reflex score was used to evaluate the colonic sensitivity of rats in each group. The repair effect of pogostone on the intestinal mechanical barrier damage in rats of each group was verified by detecting the changes in the serum D-lactate concentration and diamine oxidase activity in rats. The results of the cell experiments indicated that compared to the model control group, the pogostone (44.85, 33.64 μg/mL) treatment groups significantly increased cell viability (P < 0.01, P < 0.05); the concentration of FITC-dextran 4kDa in the pogostone(44.85 μg/mL) treatment group was significantly reduced(P < 0.05); the expression of occludin protein in barrier-damaged cells in the pogostone (44.85, 33.64 μg/mL) treatment groups was significantly increased(P < 0.01, P < 0.05), and the expression of ZO-1 protein was significantly increased(P < 0.01, P < 0.02). The molecular docking results showed that pogostone had good binding with both occludin and ZO-1 proteins. The results of animal experiments indicated that the high, medium, and low dose groups of pogostone could improve the overall condition of rats with diarrhea-predominant irritable bowel syndrome model, the colonic sensitivity in the high-dose pogostone group was significantly reduced (P < 0.05); the serum D-lactic acid concentration of rats in the high dose group of pogostone was significantly reduced (P < 0.05), and the serum diamine oxidase activity of rats in the high and medium dose groups of pogostone were decreased (P < 0.001, P < 0.001). In summary, pogostone can repair the damaged cell barriers by increasing the expression of tight junction proteins, thereby effectively restoring the intestinal mechanical barrier function of rats with diarrhea-predominant irritable bowel syndrome.