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For centuries, nonsteroidal anti-inflammatory drugs (NSAIDs) have been part of our clinical practice. They started out as drugs with anti-inflammatory and analgesic action, and gradually their use has been expanded to new therapeutic targets, some of which are unrelated to their primary mode of action. Today, our armamentarium includes a large range of compounds, attesting to their utility in the treatment of clinical pathologies ranging from pain and inflammation to prevention and treatment of cancer. On the other hand, although NSAIDs share many common properties, their use poses risks, and physicians should be cognizant of their subtle differences and potential complications. In this context, this review article presents insight into NSAIDs’ pathophysiology and mode of action in the clinical setting, their indications, and their potential side effects.