Pomegranates are known for being rich in polyphenols and are considered to have immense therapeutic potential. The present study investigates the hypothesis that the Methanolic Extract of Pomegranate (PME), a rich source of antioxidants, may reverse the adverse effects of TNF-α in endothelial cells. This was done by pre-treating the endothelial cells EA.hy926 with PME (80 µg/ml) before subjecting them to apoptotic stimuli, which was TNF-α in combination with cyclohexamide. PME was found to rescue a population of cells from apoptosis induced by TNF-α modulating the levels of BCL2 and BAX involved in intrinsic apoptotic pathway. PME was found to increase the BCL-2/BAX ratio and reverse the elevated levels of effector caspase and thus assist cells to escape from apoptotic stimuli. Also, the extract was found to attenuate oxidative stress by reducing the levels of Reactive Oxygen Species (ROS). Supplementing its anti-atherosclerotic potential, PME pre-treatment diminished the elevated levels of adhesion molecules like VCAM upon TNF-α treatment. PME may therefore have therapeutic implications in protecting the endothelium from TNF-α triggered atherosclerosis.