Peroxisome proliferator-activated receptors (PPARs), functioning as nuclear receptors, regulate the expression of genes associated with inflammation, lipid metabolism, and glucose metabolism. The primary isotypes of PPARs are PPARalpha, PPARbeta, and PPARgamma. PPARgamma is mostly expressed in adipose tissue and the colon. The activation of PPARgamma modulates signaling pathways associated with metabolism and inflammation. Inflammatory bowel diseases (IBDs) include Crohn's disease and ulcerative colitis (UC). Ulcerative colitis is predominantly localized to the colon. Considering PPARgamma's expression profile and its role in alleviating inflammation, there exists an opportunity to explore pharmaceutical targeting in the colon to diminish inflammation. We conducted molecular docking and dynamics investigations utilizing Morin hydrate (MH), a flavonoid derived from the Moraceae family, with the cocrystal structure of PPARgamma and Nrf2. They demonstrated a consistent interaction. Consequently, we conducted comprehensive preclinical studies of these interactions utilizing both in vivo and in vitro models of colon inflammation. Our findings showed that MH reduced the disease activity index, colon length shortening, and myeloperoxidase enzyme activity in mice treated with dextran sodium sulfate (DSS). MH also safeguarded colon histology by reducing proinflammatory cytokines. MH induced Nrf2 nuclear translocation, enhanced antioxidant response, and elevated Nrf2 promoter activity. MH selectively enhanced PPARgamma protein expression while leaving other PPAR isotypes unaffected. HT-29 cells, treated with tumor necrosis factor-alpha (TNFalpha) as an in vitro model of colon inflammation, exhibited a reduction in proinflammatory chemokines with exposure to MH. MH also enhanced PPARgamma promoter activity. These findings demonstrate that MH is a potent agonist of Nrf2 and PPARgamma, resulting in reduced colon inflammation.