Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition that encompasses ulcerative colitis (UC) and Crohn's disease (CD). Targeting both inflammation and the epithelial barrier simultaneously can significantly improve symptom management in IBD, as a promising strategy. In this study, we focused on addressing both inflammation and the epithelial barrier. Until now, each therapeutic target including phosphodiesterase 4 (PDE4) and prolyl hydroxylase domain enzymes 1 and 2 (PHD1/2) have been studied separately. PDE4 plays a key role in the inflammatory process by converting cyclic AMP (cAMP) to AMP and its inhibition can suppress the production of inflammatory cytokines. Research has shown that inhibiting PHD1 and PHD2 increases levels of hypoxia-inducible factor-alpha (HIF-α), which in turn strengthens the epithelial barrier by promoting the expression of protective factors such as mucins and β-defensins. Through virtual screening, molecular docking, and molecular dynamics simulations, we identified five compounds-Cassiamin C, Ginkgetin, Hinokiflavone, Sciadopitysin, and Sojagol-as promising new drug candidates for IBD treatment. All compounds demonstrated superior free binding energy for the three targets compared to reference ligands, except Sojagol concerning PDE4B. Among these compounds, Ginkgetin was the best compound with potential ability of targeting multiple drug target proteins. Future experimental studies are warranted to validate these findings.