The integrity of gastric barrier derives from the balance between defending and damaging factors. In particular, prostaglandins play a relevant role in the maintenance of gastric homeostasis and prevention of peptic disease, at different levels. Omega-3 fatty acids, particularly eicosapentanoic acid, are the precursors of the third series of prostaglandins (with anti-inflammatory properties), also reducing the formation of the second series of prostaglandins (pro-inflammatory ones). Such a pathophysiological rationale brought to the experimental application, both in animal models and, more recently, in humans, of omega-3 fatty acids against gastrointestinal damage. Omega-3 fatty acids have shown interesting results in preventing different types of gastric damage in mouse models. A large retrospective case-control study on patients taking both anti-thrombotic therapy and eicosapentanoic acid showed (although only at unadjusted analysis) an inverse correlation between consumption of eicosapentanoic acid and gastrointestinal injury. Prospective, well-designed, comparative studies are warranted to clarify if omega-3 fatty acids may represent, or not, a novel resort against gastrointestinal injury.