Osteoarthritis represents a huge socioeconomic burden and has a significant impact on daily life and productivity. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of osteoarthritis to curb inflammation, pain, and stiffness and improve physical function. However, due to the various side effects, most healthcare professionals avoid using NSAIDs for a long period. Nonselective cyclooxygenase (COX) inhibitors and cyclooxygenase-1 (COX-1) inhibitors are associated with increased gastrointestinal adverse effects due to the inhibition of prostaglandins, which are responsible for protecting the gastric mucosa. Cyclooxygenase-2 (COX-2) inhibitors are associated with an increased incidence of adverse cardiovascular effects due to their COX-2 inhibitory activity in the circulatory system. Therefore, there is a need for a newer NSAID that has a better safety profile to be used in osteoarthritis. Polmacoxib is a new, orally active, first-in-class NSAID that is a dual inhibitor of COX-2 and carbonic anhydrase (CA). The dual mode of action exhibited by polmacoxib is expected to minimize adverse cardiovascular effects while achieving maximum effectiveness in inflamed osteoarthritic joints. This article aims to review the pharmacological properties, clinical efficacy, and safety data of polmacoxib in osteoarthritis.