Eight randomized trials containing a total of 2096 patients with osteoarthritis were included in this systematic review and meta-analysis comparing topical and oral non-steroidal anti-inflammatory drugs (NSAIDs). Pooled outcomes of interest included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness sub-scores, pain on a Visual Analog Scale (VAS), and the odds of skin adverse reactions, gastrointestinal adverse reactions, and any adverse event. The results of the meta-analysis found no differences in pooled WOMAC pain, WOMAC stiffness, VAS pain scores, and odds of any adverse event between the two formulations. The pooled odds of gastrointestinal adverse reactions were higher in the oral group, while the pooled odds of skin adverse reactions were higher in the topical group.