This study aimed to investigate the efficacy of fexuprazan in restoring intestinal barrier function in comparison with other potassium-competitive acid blockers (P-CABs) and esomeprazole. The effect of fexuprazan on trans-epithelial electrical resistance (TEER) value, mRNA and protein expression of tight junction genes, and cell morphology was investigated using a dextran sulfate sodium (DSS)-induced ulcerative colitis Caco-2 cell model. Treatment with fexuprazan, esomeprazole, tegoprazan, and vonoprazan significantly increased TEER values in a 3 % DSS-induced ulcerative colitis Caco-2 cells in a concentration-dependent manner. The TEER value-concentration profile showed sigmoidal shape curves and yielded half maximal effective concentration of 0.983 - 1.17 μg/mL for P-CABs and 3.27 μg/mL for esomeprazole. Among these drugs, fexuprazan showed the highest activity in the restoring intestinal barrier function. Fexuprazan also increased the expression of tight junction genes including zonula occludens-1, claudin 1, occludin, and mucin 1, and also thickened the epithelial cell membrane after treatment with 20 μg/mL fexuprazan. Fexuprazan showed a particularly high distribution in the liver and gastrointestinal tract in rats following oral administration of 2 mg/kg fexuprazan, which appears to be a positive characteristic of fexuprazan's effect on ulcerative colitis and gastric acid-related diseases although in vivo therapeutic efficacy of fexuprazan for ulcerative colitis requires further validation in both animal and human. In conclusion, fexuprazan can potentially restore intestinal barrier function by increasing the expression of tight junction genes and by strengthening the cell membrane integrity in DSS-induced colitis model.