For decades, evidence-based data and reported experience have warned that the common chronic oral nonsteroidal anti-inflammatory drug (NSAID) therapy for osteoarthritis (OA) in elderly patients is ultimately dangerous. Elderly patients with OA are at heightened risk for developing serious gastrointestional and cardiovascular adverse events, including gastrointestinal bleeding, myocardial infarction, and stroke. Prescribing NSAIDs, especially in an elderly population, continues to be discouraged because of these significant risks. A dilemma exists for individuals who need the established efficacy associated with oral NSAIDs but who are at increased risk for serious adverse events associated with these agents. The goal of this clinical review was to evaluate the risks versus benefits of current options in the treatment of OA. This review found that topical NSAIDs seem to be the safest choice among all options to mitigate gastrointestinal and cardiovascular risks and should be considered prior to the initiation of oral nonselective or cyclooxygenase (COX)-2-selective NSAIDs for individuals presenting with a localized expression of OA. Further research is needed to evaluate and compare these therapies in treating both pain and inflammation effectively while mitigating safety risks in high-risk populations.