Vitis vinifera (grape) is one of the "most-produced fruit" in the world. Grape seeds are a valuable source of phenolic compounds including resveratrol (RSV). Grape and one of its biologically active constituents, RSV, exert their protective effects against different natural or chemical toxins which could alter physiological homeostasis through a variety of mechanisms. Some of these mechanisms of actions include increase in superoxide dismutase, hemeoxygenase-1, and glutathione peroxidase activities and reduced glutathione content and decrease in malondialdehyde (MDA) levels and activation of the nuclear erythroid2-related factor2/ARE pathway. There are also various reports of the potential use of such compounds in preventing different ailments including cardiovascular diseases, cancer, degenerative diseases, and inflammatory disorders. Therefore, in this review, we have investigated the possible protective effects of grape and one of its biologically active constituents, RSV, on different organs' toxicity induced by natural toxins (such as mycotoxins, lipopolysaccharide, and triptolide) and chemical toxins (such as antitumors, metals, and carbon tetrachloride). There are insufficient clinical trials on this subject, so our review only includes in vivo and in vitro studies. To establish the grape beneficial effects in human intoxication, more clinical trials need to be accomplished.