Osteoarthritis (OA) is the most common form of degenerative arthritis, mainly characterized by the degradation of articular cartilage and associated with subchondral bone lesions. Novel therapeutic approaches for OA include cell-based therapies that have become thriving areas of research and development. In this context, mesenchymal stem or stromal cells (MSCs) have gained much interest based on their trophic and immunomodulatory properties that can help tissue repair/regeneration. The present review article discusses the interest of using MSCs in cell-therapy approaches with a focus on the mechanisms by which MSCs might exhibit a therapeutic potential in OA. Special attention is given to the anti-inflammatory function of MSCs and on miRNA modulation in OA for possible future innovative strategies. The paper also presents the current data on the undergoing MSCs-based clinical trials in OA.