Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used nonaddictive medications for the management of chronic pain and inflammation; however, these drugs are associated with many gastrointestinal and cardiovascular adverse events, including intestinal bleeding, ulceration, stenosis, myocardial infarction, and stroke. It has long been accepted that NSAID enteropathy is an unavoidable consequence of simultaneously inhibiting both cyclooxygenases (COX) -1 and -2 to suppress prostaglandin synthesis. Operating under this assumption, I had developed a novel mouse model of inducible COX-1 + COX-2 deletion to complement our lab’s chronic NSAID exposure model. These COX double-knockout mice exhibited substantially suppressed prostaglandin levels comparable to (and often lower than) those of wildtype mice treated with the nonselective NSAID naproxen. Yet surprisingly, the COX double-knockouts never spontaneously developed any gastrointestinal damage when tracked for an entire year, whereas the naproxen mice consistently exhibit gastric and intestinal lesions and bleeding within 3 weeks. Moreover, upon administering naproxen to the COX double-knockout mice, they do develop gastroenteropathy, despite lacking the intended drug target and exhibiting no change in prostaglandin levels from baseline. The same pattern is observed when these mice are treated with phenylpropionic acid, a compound that bears a similar structure to naproxen yet has no COX activity. These results challenge the prevailing dogma that attributes NSAID enteropathy to prostaglandin inhibition, robustly demonstrating that prolonged suppression of prostaglandin synthesis alone is not sufficient to induce gastrointestinal damage. Rather, mechanisms specific to the drug (including topical irritation of the intestinal epithelium, mitochondrial dysfunction, enterohepatic recirculation, and prolonged exposure to bile acids) appear to be required as the dominant insult or a double-hit. With a better understanding of how NSAIDs elicit intestinal damage, these studies ultimately aim to improve enteric NSAID tolerance in patients. They may afford insights that allow for the design of safer pharmaceuticals or drug combinations that widen the therapeutic index of a commonly consumed class of drugs.