Osteoarthritis (OA) is a chronic degenerative disease that affects the whole synovial joint. OA causes severe pain and disability that significantly affects the livelihood of an individual and incurs a huge socioeconomic burden. Current management strategies are limited to supporting functional improvement with physiotherapy and pain reduction as there are no drugs available that can reverse the progression of OA with only joint replacement surgery for late stage OA. OA is associated with advancing age and obesity, both of which compromise the functions of key endoplasmic reticulum (ER) molecular chaperones leading to improper protein folding and ER stress. Failure to restore protein homeostasis leads to increased cellular stress and eventually apoptotic cell death. Cartilage is avascular and is dependent on its constituent cells, chondrocytes, for extracellular matrix maintenance. Chondrocytes have limited proliferative capacity and their apoptosis eventually leads to extracellular matrix loss and cartilage degeneration. Recent studies on attenuating ER stress and chondrocytes apoptosis offer a credible strategy for reducing OA progression. The established roles of ER stress responses in OA have paved the way for targeted drug discovery studies aiming to mitigate ER stress and OA progression. In this review, in vitro, pre-clinical and clinical evidence of naturally-derived ER stress inhibitors for OA, the prospect and challenges in bringing these compounds to clinics are discussed.