Arthritic diseases have attracted enormous scientific interest because of increased worldwide prevalence and represent a significant socioeconomic burden. Osteoarthritis (OA) is the most prevalent form of arthritis. It is a disorder of the diarthrodial joints, characterized by degeneration and loss of articular cartilage associated with adjacent subchondral bone changes. Chronic and unresolving inflammation has been identified as a critical factor driving joint degeneration and pain in OA. Despite numerous attempts at therapeutic intervention, no effective disease-modifying agents targeting OA inflammation are available to the patients. Inflammasomes are protein complexes known to play a critical role in the inflammatory pathology of several diseases, and their roles in OA pathogenesis have become evident over the last decade. In this sense, it is relevant to evaluate the vital role of inflammasomes as potential modulators of pathogenic features in OA. This review will provide an overview and perspectives on why understanding inflammasome activation is critical for identifying effective OA therapies. We elaborate on the contribution of extracellular mediators from the circulatory system and synovial fluid as well as intracellular activators within the synovial fibroblasts and articular chondrocytes toward invoking the inflammasome in OA. We further discuss the merits of emerging inflammasome targeting therapies and speculate on the potential strategies for inflammasome blockade for OA therapy.