Resveratrol protects against organ injury caused by trauma-hemorrhage, although the mechanism remains unknown. We have previously shown that it exerts protective effects in the liver via estrogen receptors and their signaling. Thus, we set out to determine whether resveratrol-mediated estrogen receptor-dependent p38 mitogen-activated protein kinase (MAPK)/heme oxygenase 1 activation protects the intestine after trauma-hemorrhage. To study this, male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure, ~ 40 mmHg for 90 min) followed by fluid resuscitation. Animals were pretreated with an estrogen receptor antagonist (ICI 182,780), a specific p38 MAPK inhibitor (SB-203580), or a heme oxygenase enzyme antagonist (chromium-mesoporphyrin) 30 min before vehicle or resveratrol (30 mg/kg) administration, followed by resuscitation, and were killed 2 h thereafter. Intestinal water content, myeloperoxidase activity, and TNF-α, IL-6, intercellular adhesion molecule 1, cytokine-induced neutrophil chemoattractant (CINC) 1, and CINC-3 levels and edema of the lung were measured. Mean arterial blood pressure, cardiac output, positive maximal pressure of left ventricular increase (+dP/dtmax), and negative maximal pressure of left ventricular decrease (-dP/dtmax) were also determined. Intestinal p38 MAPK activity and heme oxygenase 1 expression were also determined. Trauma-hemorrhage led to an increase in intestinal water content, myeloperoxidase activity, and TNF-α, IL-6, intercellular adhesion molecule 1, CINC-1, and CINC-3 levels. This was accompanied by a decrease in intestinal p38 MAPK activity. Administration of resveratrol improved all of the above parameters. Resveratrol treatment also increased intestinal heme oxygenase 1 expression as compared with vehicle-treated trauma-hemorrhaged rats. Administration of ICI 182,780, SB-203850, or chromium-mesoporphyrin with resveratrol abolished the resveratrol-mediated improvement of the above parameters. Resveratrol administration also attenuated trauma-hemorrhage-induced cardiac dysfunction and edema of the lung. These results suggest that estrogen receptor-dependent upregulation of the p38 MAPK/heme oxygenase 1 pathway plays a critical role in mediating the salutary effects of resveratrol on shock-induced intestinal injury.